Important note: Information in this article was accurate in August 2000. The state of the art may have changed since the publication date.
These incidents are but the latest chapters in a long story. Almost since AZT was introduced in 1987, scientists have recognized that nucleoside analogs are not very specific. They attack HIV, but they are toxic to cells, too, sometimes with life-threatening consequences.
Nucleoside analogs like ddI, d4T, lodenosine or the similar nucleotide analogs such as adefovir together form the class of antiretroviral drugs known as NRTIs (nucleoside reverse transcriptase inhibitors). NRTIs work against HIV by disrupting the function of the virus’s reverse transcriptase enzyme, which converts the HIV gene set into a DNA form that is then inserted into human cell genomes. Nucleoside and nucleotide analogs are defective versions of the natural building blocks of DNA. Normal nucleosides are first phosphorylated into nucleotides and then chained together to form DNA by both reverse transcriptase and the cells’ own enzymes.
NRTIs lack the molecular hooks needed to continue this process. They terminate the chain being constructed by reverse transcriptase and block the infection of new cells. NRTIs generally do not affect construction of new cellular DNA because the enzymes that drive this process in cell nuclei have a “proofreading” mechanism. It snips out NRTIs if they are inserted into a new DNA chain. There is an exception to this rule, though: The cells’ weak point lies in the mitochondria, the energy-producing components of the cell.
Eons ago, at the dawn of evolution, mitochondria apparently were independent bacteria-like cells. At some point, they took up abode in larger, more advanced cells with nuclei and entered into a symbiotic relationship. Today, mitochondria exist as partially autonomous organelles within nearly all nonbacterial cells. They take the form of small pouches of deeply folded membranes. Enzymes on these membranes oxidize sugar and fat to create the energy that cells utilize for their myriad chemical processes.
Hundreds of mitochondria exist in each cell and replicate independently of the cell’s own proliferation. The existing mitochondria are doled out to the daughter cells during mitosis (cell division); the mitochondria then replicate in each cell according to the cell’s energy needs. As part of their semi-independent existence, mitochondria retain certain genes. These govern production of about 3% of their proteins and enzymes. Two to ten redundant copies of the mitochondrial genome exist within each mitochondrion in the form of circular double-stranded DNA.
Mitochondrial genes are particularly prone to damage. DNA polymerase gamma, the enzyme that directs replication of the mitochondrial genes, is more primitive than the DNA polymerase enzymes in the cell nucleus. Polymerase gamma has no “proofreading” function, so little repair of errors occurs when stringing nucleotides together. NRTIs therefore inhibit DNA polymerase gamma to a certain extent, in a manner that parallels their effect on reverse transcriptase.
Mitochondria rely on their genetic redundancy to protect against dangerous errors in their genes. Faulty DNA coexists and replicates alongside accurately reproduced DNA, which covers for the defect. Similarly, working mitochondria can compensate for defective mitochondria within the same cell.
The system breaks down only when damaged mitochondrial DNA reaches a threshold proportion somewhere above 70%. Cells then begin to suffer from energy deficiencies and turn increasingly to anaerobic processes (i.e., without using oxygen) outside the mitochondria. Anaerobic respiration is much less efficient than mitochondria’s oxidative process and produces lactic acid, an acidifying substance that severely perturbs blood chemistry.
Mitochondrial oxidation can give rise to toxic byproducts, too. These are reactive oxygen species (ROS). These highly reactive forms of oxygen (O2–, H2O2 and OH) damage DNA and other molecules. They appear at elevated levels when energy production is inhibited at mid-stage. Antioxidant molecules (superoxide dismutase and glutathione) within mitochondria are supposed to eliminate ROS by reducing them to water while transferring their extra electrons to metals. This process is not always effective enough to prevent oxidative stress. An accretion of dysfunctional mitochondria due to ROS degradation of mitochondrial DNA is thought to be one of the processes central to aging.
Specific disease syndromes are also connected with rare inherited mitochondrial mutations. Mitochondria-related diseases vary in severity from person to person, and symptoms frequently appear only as a person ages. Tissues such as muscles and nerves, which require high levels of energy, are most often involved. Some of the specific conditions related to inadequate mitochondrial activity are muscle wasting (myopathy); heart failure (cardiomyopathy); peripheral numbness and pain (neuropathy); generalized loss of the kidney's ability to filter the blood (proximal renal tubular dysfunction or Fanconi-like syndrome); low blood cell counts (anemia, leukopenia, thrombocytopenia or pancytopenia); swelling and fatty degeneration of the liver (hepatomegaly with steatosis); and pancreatic inflammation (pancreatitis). Fatigue, psychological depression and high lactic acid levels (lactic acidosis) are more generalized signs.
Researchers reported a connection between myopathy and AZT in 1990.2 A year later came a paper associating AZT with heart muscle damage in particular. 3 Other signs of mitochondrial toxicity were associated with nucleoside analogs in the years that followed. It is rather mysterious why different NRTIs have different effects and why different individuals have varying sensitivity to those effects. The variations between individuals may relate to the mitochondrial mutations already present and to their distribution in various organs, which is not necessarily uniform.
The varying sensitivity of different tissues to specific NRTIs presumably arises from variations in the penetration of those drugs in different cells and the energy requirements of those cells. For example, adefovir selectively and severely affects kidney cells because it binds to the kidney cell transporter molecule hOAT1.4 This binding causes adefovir to build up inside the cells lining the walls of renal tubules, where unwanted compounds are transferred from the blood to the urine.
d4T and ddC represent two critical cases in which mitochondrial-associated toxicity—in both of these cases, neuropathy—was so severe that doses had to be greatly restricted during research and development. In the lab, both compounds proved to be highly potent antiretroviral agents. Human trials of d4T originally included daily doses as high as 900 mg. Volunteers reported immediate improvements in their health, but two-thirds rapidly had to abandon the drug because of intolerable neuropathy. In the end, the committee monitoring the large d4T parallel track program found that even 40 mg twice daily was too much. About a quarter of the persons taking this dose quit the parallel track program because of neuropathy. The development of neuropathy was more common among people with lower CD4 cell counts. Peripheral neuropathy also developed after an average of 79 weeks in one-half of the participants in a d4T monotherapy trial who received 40 mg twice daily. Nonetheless, 40 mg twice a day became the standard dose.
The official FDA-approved package inserts for all nucleoside analogs carry a prominent warning to the effect that: “Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors.” This hepatic degeneration recalls the “acute fatty liver” of pregnancy, a maternal syndrome that threatens both mother and fetus and results from an inherited fetal inability to oxidize fatty acids in the mitochondria..5
The liver degeneration warnings are based on isolated incidents that occurred after drug approval. It is difficult to say how frequent they are now. A 1989-1994 review of Johns Hopkins' HIV Clinic patients recorded an incidence of 1.3 per 1,000 patient-years for severe cases of hepatomegaly with steatosis and lactic acidosis.6 A more recent French study found a frequency of 8.4 per 1,000 patient-years for “symptomatic” high lactic acid levels. 7
In the case of ddI, the incidence of serious pancreatitis has decreased in recent years, as patients' overall health improved with the success of potent anti-HIV regimens. Frequent monitoring to detect the presence of pancreatic enzymes in the blood can provide an early warning of incipient pancreatitis. But this condition sometimes develops rapidly and without forewarning, after doctors may have stopped paying careful attention. It is unsettling that, as with other mitochondrial toxicities, the precise risk factors predisposing an individual on ddI to pancreatitis remain unexplored after more than a decade of testing and marketing. The effects of combining ddI with other drugs such as d4T and hydroxyurea similarly have come as a surprise.
The FDA continues to receive reports of deaths from lactic acidosis, 8 and unrecognized fatigue associated with mild increases in lactic acid levels may be much more common than severe cases.6 A recent study of HIV clinic patients in Vancouver found that lactic acid levels were elevated in 20.5% of 331 treated patients,9 and 8.1% of the 331 had seriously high levels.
The classic symptoms of NRTI-induced lactic acidosis, nausea, abdominal pain and fatigue, are vague. Two standard lab measurements, lactic acid levels and exercise capacity, are by themselves fairly nonspecific, since they may result from pulmonary insufficiency as well as mitochondrial damage. Other signs to watch for include increased breathing rate with decreased oxygen uptake 10 and such indications of tissue damage as high blood levels of pancreatic, muscle and liver enzymes. 11
The liver is central to the lactic acidosis associated with NRTIs since it is supposed to eliminate lactic acid from the blood. Beyond measuring blood levels of liver enzymes, computed tomography (CT) or ultrasound scans are useful in detecting fatty degeneration of the liver. The most specific test for mitochondrial toxicity involves analyzing a 24-hour patient urine sample for particular intermediate metabolites that appear when oxidation is blocked and carbohydrates, fats and amino acids only partially broken down. Such sophisticated testing is not part of a standard medical work-up, however.
After our long experience with one nucleoside analog or another, we now have potent three or four drug combinations that include protease inhibitors or nonnucleoside reverse transcriptase inhibitors (NNRTIs) as well as NRTIs. Combining these drugs also combines their toxicities in ways that we have not yet experienced. More importantly, the antiviral drugs will now be taken for much longer periods of time than in the past. With the durable suppression of HIV wrought by highly active antiretroviral therapy (HAART), health has stabilized but residual HIV survives. Not only do we have a new era in HIV therapy; we have a new era in long-term toxicities.
Chronic unsuppressed HIV infection was always noted for triggering a wasting syndrome in which people with HIV lose lean tissue mass, sometimes to a life-threatening extent. Some researchers observed that subcutaneous fat loss accompanied the loss of lean tissue, especially in women and overweight men. 12 The worst deficiency, it appeared, was an inability to regain lean mass lost during major opportunistic infections.
Today, many people taking HAART have trouble maintaining or restoring proper fat distribution. Fat tends to accumulate over time around the central organs and sometimes around the back or front of the neck. Meanwhile, there is continued depletion of subcutaneous fat stores (lipoatrophy), especially in the limbs and cheeks.
This widespread body fat rearrangement (affecting up to two-thirds of participants in various studies 13 has been a curious phenomenon. It was assumed at first that the new protease inhibitors were responsible for this “lipodystrophy,” which received the popular sobriquets “Crix belly” or “protease paunch.”
After the first flood of reports, physicians began to recall that they had seen some cases of fat accumulation at the base of the neck and between the shoulder blades in the pre-HAART days. (These dorsocervical fat pads are commonly called “buffalo humps.”) At times, the doctors had noted lipoatrophy along with this buildup. There also is a marked similarity between HAART-associated lipodystrophy and a form of multiple symmetrical lipomatosis (abnormal fat accumulations), also known as MSL or Madelung's disease. Both syndromes involve peripheral fat loss and buffalo humps. Persons with MSL do not have fat deposits in the torso, though they do exhibit neuropathy. Several reports indicate that mutations at a particular point in the mitochondrial DNA accompany MSL.
A recent survey of body fat abnormalities in Australia's HIV-positive population recorded an overall prevalence of 54%, including 63% of those who had taken protease inhibitors and 32% of those with exposure to treatments that did not include PIs.14 The same research group, headed by Andrew Carr, MD, and David Cooper, MD, of St. Vincent's Hospital in Sydney, went on to compare three separate “control” groups without lipodystrophy to 14 men receiving NRTIs only and experiencing peripheral fat loss with or without fat accumulation. 15 These three control groups comprised 32 treatment-naïve men, 28 men on NRTIs only and 44 men receiving NRTIs plus protease inhibitors. A fourth comparison group contained 102 men with lipodystrophy who were taking both NRTIs and protease inhibitors.
The NRTI-only cases of lipodystrophy were distinguished by higher lactic acid levels, which correlated with losses in body weight and signs of liver dysfunction. These signs included swollen livers and elevated liver enzymes in the blood, all of which are suggestive of mitochondrial toxicity.
Liver toxicity has particular implications for aggravating mitochondrial toxicity since the liver removes lactic acid from the blood. Liver function is critical for fat metabolism, too, given that organ's central role in converting excess blood lipids into glucose or vice versa as required by the body's activity level and dietary intake. Reduced liver activity can lead to high lipid and sugar levels and result in a high-insulin diabetic condition.
Recent weight loss, fatigue and nausea were significantly more common in the Australians' NRTI lipodystrophy group than in the combined-therapy lipodystrophy group. The lipodystrophic men on protease inhibitors had higher blood levels of lipids (cholesterol and triglycerides), glucose and insulin than did their counterparts on NRTIs only.
Body shape alterations were similar in the two groups. This was not the case, though, in a similar French study. 16 The French researchers found that those on PI-containing regimens had markedly more deep visceral fat than those either on NRTIs only or taking no anti-HIV drugs. Both the PI and NRTI groups had about the same amount of subcutaneous fat, which was substantially less than in the treatment-naive group.
Significant risk factors for lipodystrophy in the Australian study included current use of d4T and the number of years on any nucleoside analog. Each year of nucleoside analog use increased the risk of lipoatrophy 1.26-fold. In contrast, each year of protease inhibitor use tripled the risk of any form of lipodystrophy. Discontinuing NRTIs led to reductions in blood lactic acid and liver enzymes, nausea and fatigue, but lost weight was not recovered (over an average four months of follow-up).
The French study also found a strong connection between lipoatrophy and d4T. In 1999, the same researchers reported what happened when 29 persons with peripheral fat wasting were taken off d4T and switched to another drug(s) 17 Fourteen who were also receiving a protease inhibitor changed from d4T to AZT or abacavir. The rest replaced their d4T-containing NRTI regimen with AZT/3TC/nevirapine. After six months, blood triglycerides decreased by about 40% in both groups while subcutaneous fat rose 40%.
The Vancouver clinic study mentioned above found that elevated lactic acid levels were associated with current use of d4T or hydroxyurea and total time on d4T. Glaxo Wellcome, the maker of AZT, 3TC and abacavir, is quick to point to studies like these. Whether d4T is especially culpable in lipoatrophy or mitochondrial toxicity has yet to be decisively documented, however. Most persons on d4T have taken AZT previously and have lived longer with HIV infection.
Likewise, laboratory studies that attempt to rank the respective mitochondrial toxicity of different NRTIs are open to question since they may not reflect what happens in living cells in the body. There, toxicity is determined not just by the drugs' chemical inhibition of DNA polymerase gamma, but also by the concentration of each compound within mitochondria and the ease with which it is activated by adding three phosphate groups before DNA polymerase can process it.
The energy demands that cells in the body put on their mitochondria are yet another decisive factor in eliciting the NRTIs' inhibition of mitochondrial activity. Gender and HIV infection itself are major factors that influence the metabolic and, hence, the energy profile of cells throughout the body.
NRTIs also may have other effects on mitochondrial metabolism besides interference with DNA replication. For example, although lodenosine seemed to have little effect on mitochondrial DNA in lab tests, it caused serious heart toxicity in mice and fatal liver toxicity in humans in a way that resembles mitochondrial failure. This nucleoside analog in fact does disrupt mitochondrial functioning, as evidenced by the heightened lactic acid levels and death in laboratory cell lines exposed to it 18 According to Yung-chi Cheng, a Yale University researcher who did the original mitochondrial assays on lodenosine, its toxic effect probably results from inhibition of lactic acid dehydrogenase, an enzyme that converts lactic acid into a compound that the mitochondria can oxidize.
A parallel situation exists for AZT, claims a recent study conducted in a laboratory liver cell line by Jean-Pierre Sommadossi, PharmD, and colleagues from the University of Alabama 19 AZT did not inhibit mitochondrial DNA synthesis, unlike ddC and ddI, but it did increase lactic acid production in cell cultures whereas other nucleoside analogs did not. The researchers found that exposure to AZT directly reduced the activity of several of the mitochondria's major energy-producing enzymes. This was thought to be the reason for the contradictory results.
At this past spring's Keystone Symposium on New Biological Approaches to HIV-1 Infection, Scott Raidel and William Lewis of the Department of Pathology at Emory University showed striking photos of mitochondria in the heart muscle of mice bioengineered to produce HIV's Tat protein.20 The mitochondria were extremely elongated and their internal structure disrupted. Their mitochondrial DNA content was about 30% lower than in normal mice.
When NRTIs enter the body, they encounter an environment that already may be prone to the type of mitochondrial damage that these drugs promote. Tat is a protein that helps convert the HIV DNA genome within cells back into RNA for packaging in a new generation of viruses. Among other things, it suppresses the cells' antioxidant protective system, rendering them more sensitive to inflammatory activation by such cytokines as tumor necrosis factor (TNF). (Cytokines are intercellular messenger proteins that coordinate immune system responses.) Uninfected cells in lymph nodes are chronically exposed to Tat and suffer the effects of oxidative stress. Many die with swollen, disrupted mitochondria.21
The metabolic effects of TNF production under the stimulation of chronic HIV have been blamed for wasting. Doctors have also noted cases of neuropathy and muscle weakness that seem caused by HIV infection itself and not by drugs or opportunistic infections. Mitochondrial disturbances possibly contribute to these.
The nonmitochondrial effects of other drugs also play a role in enhancing the toxicity of NRTIs. In a 2,100-person French cohort, 22 the incidence of severe liver toxicity after one year on one or two protease inhibitors plus two nucleoside analogs was 7.9%. By comparison, 4.8% of those on only two nucleoside analogs experienced a similar problem. No individual drugs stood out as particularly risky in this study.
Nevirapine, an NNRTI with no known mitochondrial effects, also causes significant liver toxicity. In April, the European Medicines Evaluation Agency (EMEA), the European Union's version of the FDA, issued a special warning on the subject. The agency called for increased monitoring of liver function, especially during the first two months of nevirapine therapy.
At the same time, the South African government's Medicines Control Commission (MCC) halted further enrollment in a trial involving nevirapine, d4T and the experimental nucleoside analog FTC. Seven cases of hepatitis, six of them in women, occurred among the 394 persons receiving nevirapine. Two of the people who contracted hepatitis died.
The Ministry of Health initially blamed nevirapine for the higher than expected rate of serious liver dysfunction. Yet as the MCC quickly pointed out, it is not clear which drug was at fault. An interaction between nevirapine and d4T, and perhaps all three drugs, may well have been the cause of the liver problems. Isolating each drug's individual role will be difficult.
Protease inhibitors also derange lipid metabolism. One clear-cut study gave the PI ritonavir or placebo to 21 HIV-negative men for two weeks.23 At the end of two weeks, the 11 men on ritonavir had sharply increased blood lipids: Cholesterol levels rose 24%, and triglycerides shot up 145%. Surveys13, 14 comparing treatment-naïve persons with HIV to those on nucleoside analogs or nucleoside analogs plus protease inhibitors have observed similar cholesterol and triglyceride elevations in the PI group. They also noted that the persons receiving protease inhibitors had greater abdominal or visceral fat than the others.
Lipodystrophy may not be a single syndrome. Peripheral fat wasting and buffalo hump could be due to NRTIs and their mitochondrial toxicity while PIs might further perturb liver and fat-cell processing of lipids, leading to high blood cholesterol and triglycerides and truncal fat accumulation as well.
The drugs' side effects may be deeply intertwined: Loss of sensitivity to insulin (“insulin resistance”) and diabetes frequently have been associated with protease inhibitors. A new lab study by Mike Mueckler and colleagues at the Washington University School of Medicine suggests a mechanism for this effect. Protease inhibitors reduced the insulin-triggered intake of glucose by cultured fat cells.24 Fat cells may not be able to absorb enough fat because of the protease inhibitors, and they cannot process what they do take up because the nucleoside analogs lower their overall energy levels.
Finally, Thierry Saint-Marc, MD, has observed that large treatment-induced reductions in viral load by themselves lead to high insulin levels and loss of cells' sensitivity to this sugar-regulating hormone. 16 The reverse is true during chronically high viral loads, when insulin clearance and sensitivity are heightened. Fat cells' loss of sensitivity to insulin (“insulin resistance”) results in high lipid production in the liver, which seeks to reduce sugar levels, and thence to the development of high blood lipids and fat redistribution.
In the fall of 1999, BioChem Pharma ran into trouble with its new nucleoside analog dOTC. The company had had to halt further testing because this previously promising drug was causing life-threatening inflammatory reactions in monkeys after four months of exposure. BioChem resolved the problem by switching to the L-version of this molecule. The L-molecules are mirror images of D-molecules, which are what the body uses to build DNA. L-drugs tend to be safer than D-drugs because the body's enzymes reject them more easily. They do not penetrate the mitochondria very well as a result. But L-nucleoside analogs still are able to halt the DNA-fabricating activity of HIV's reverse transcriptase in the cell nucleus.
3TC was the first marketed L-nucleoside analog, and it turned out to be relatively benign. FTC, an experimental nucleoside analog now in phase 3 testing, is another L-drug. In one laboratory study, these two L-drugs partially reversed the cell toxicities of the standard D-nucleoside analogs. 25 This perhaps was because the presence of the L-drugs inhibits the entry of D-drugs into mitochondria.
Another experimental L-nucleoside analog, L-Fd4C, hardly affected mitochondrial DNA production in lab cell cultures, and greatly reduced the reduction in mitochondrial DNA synthesis produced by the presence of ddC, ddI or d4T.26 Its affinity for HIV reverse transcriptase, meanwhile, is very high. On the other hand, it does inhibit some of the cell nucleus DNA polymerases, though this inhibition is small compared to its effect on HIV reverse transcriptase.
FTC is inactive in people whose HIV has resistance against 3TC, and L-Fd4C is a long way from the market. Both are also subject to patent disputes. While waiting for less toxic NRTIs, people with HIV have only a few real possibilities for reversing NRTIs' mitochondrial toxicities.
They obviously could switch off drugs that prove intolerable in their personal case. As mentioned above, changing from d4T to AZT or abacavir showed some benefit in one small study. But frequently, one's options are limited by HIV drug resistance, and other regimens may turn out to instigate other unacceptable side effects.
One widely advertised agent that has some effect in countering the fatigue associated with certain nucleoside analogs is erythropoietin (Procrit). Procrit is a bioengineered version of a growth factor that stimulates red blood cell production. Although it helps reverse the anemia caused by AZT, Procrit can do nothing for other sources of fatigue, including the muscle weakness and high lactic acid levels connected with mitochondrial dysfunction. Patients need to be monitored for such effects, and Procrit is no substitute for replacing the offending drug in many cases.
There are some potential but poorly researched ways to directly counteract mitochondrial toxicities. The agents involved are natural cofactors for mitochondrial energy production, and supplying them might increase the efficiency of that process. For example, there have been two one-patient reports of treating severe lactic acidosis with massive amounts of riboflavin (vitamin B2), a micronutrient that is commonly deficient in people with HIV. 27, 28 Other suggested treatments along these lines have been coenzyme Q10 and the vitamins B1 (thiamine), B12, and K.
Another agent that might reduce mitochondrial toxicity is l-acetyl carnitine. L-carnitine is a product of protein breakdown that is used to transport fat components into the mitochondria for oxidation. L-acetyl carnitine, a variant of L-carnitine, shares this function and also helps damaged nerve cells regenerate. One four-person study has now indicated that L-acetyl carnitine at 1500 mg twice a day promotes nerve growth and reduces symptoms in people with drug-related neuropathy.29 (Again, note that L-acetyl carnitine is not the L-carnitine sold in health food stores.)
A previous Italian study, led by Andrea Cossarizza of the University of Modena, of T-cells taken from people with primary HIV infection found electric charge alterations in mitochondrial membranes and noted a strong tendency for these cells to undergo spontaneous cell death.30 Such cell death correlated with patients' HIV and tumor necrosis factor (TNF) levels. In the test tube, L-acetyl carnitine, as well as N-acetyl cysteine (a component of the antioxidant molecule glutathione) and nicotinamide (a version of niacin and part of a mitochondrial energy-producing enzyme), was able to reverse the cells' aberrations.
The association of dysfunction with TNF suggested that the cell rescue involved a process that reversed oxidative stress. A Spanish study, led by José Garcia de la Asunción and colleagues at the University of Valencia, tried a similar strategy using high doses of the antioxidant vitamins C (1 g/day) and E (0.6 g/day).31 Chemical markers of muscle damage and oxidative stress decreased in eight HIV-positive persons on AZT plus the vitamins compared to a control group on AZT alone. The same was true in a group of experimental mice. Examination of the mitochondria in the mice's muscle cells further showed that the mice receiving AZT plus the vitamins retained normally organized mitochondria whereas the mice on AZT alone had swollen, disrupted mitochondria. High intake of these vitamins may have long-term toxicities of their own. In the United States, researchers like William Lewis at Emory University are searching for more efficient compounds that would obviate the need for vitamin megadosing.
The little mitochondria play a big role in the body's metabolism. Their protection is critical to sustaining life. Although an abundance of research suggests that certain NRTIs severely disrupt mitochondria, the exact significance and nature of that toxicity requires further elucidation. Development of nontoxic treatments to support energy production and of safer nucleoside analogs is paramount. But that research is still in rudimentary stages and lacks substantial industry or government support.
Worse yet, the commercial implications of present NRTIs' mitochondrial toxicity threaten to disrupt the objective scientific process. Glaxo Wellcome, for example, has stressed the dangers of mitochondrial toxicity together with the implication that its nucleoside analogs are safer than d4T and ddI, which are produced by Bristol-Myers Squibb. Ortho Biotech has seen sales of Procrit skyrocket after an enormous advertising campaign aimed at persons on antiretroviral drugs and cancer chemotherapies. The campaign included specious promotion of Procrit as the answer to HIV-related fatigue. It is a dark day indeed when scientific information is selectively marshaled to support one product over its competitors.
On balance, the experience with highly active anti-HIV regimens has of course been positive, with the annual HIV death rate dropping by two-thirds in the US. As time on treatment lengthens, that experience could take a turn for the worse. The development of better ways to monitor development of mitochondrial toxicities is vital, both for the care of individual patients and to track this side effect's overall incidence. Solid data from large cohorts would also help better define risk factors and predict who may suffer serious illness from their medication.
An improved understanding of the ways different drugs affect different organs and tissues would go a long way in advancing the management of mitochondrial toxicity and such possibly related side effects as lipoatrophy. Finally, treatments for the occasional emergency episodes are critical. The current standard response to life-threatening lactic acidosis is to stop medication and provide supportive care while waiting for recovery. This passive approach may require a three- or four-week stay in an intensive care unit, and it allows HIV levels to skyrocket.
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