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Long-Term Toxicities Associated With HIV and Antiretroviral Therapy

June 2003

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!


Introduction

Soon after the introduction of the first antiretroviral (ARV) agent, zidovudine (AZT), drug-related toxicities became recognized and well-characterized. Things have since become more complicated; there are now 17 ARV agents in four distinct classes. This has led to both decreased morbidity and mortality from HIV infection due to immune reconstitution and viral suppression, and increasing recognition of both acute and long-term toxicities of ARV therapy (ART). Most clinicians agree that the benefits of ART generally outweigh the risk; however, patients who experience significant side effects sometimes disagree with this. This can lead to patient non-adherence or refusal to take any ART at all for fear of toxicity. Drug toxicities may have both acute and long-term implications to the health of HIV-infected persons.

This report reviews common acute and long-term toxicities of ART. Drug toxicities can be class-specific or ARV-agent specific. Having an understanding of these complications allows clinicians to anticipate potential toxicities, and to communicate about them with their patients. Clinicians should inform patients considering ART what complications they may experience, how to recognize these side effects, and what they should do about them. This proactive approach is likely to lead to a more trusting relationship and improved adherence.1


Mitochondrial Toxicity

In recent years, mitochondrial toxicity has been recognized as one of the most serious potential side effects of ART.2 Mitochondria are the energy-producing factories of our bodies; when mitochondrial production is decreased by inhibition of the cellular DNA polymerase gamma, end-organ toxicity can occur. Mitochondrial toxicity is associated with the use of the nucleoside and nucleotide reverse transcriptase inhibitors, and may lead to a number of clinical problems. These include pancreatitis, peripheral neuropathy, and increased production of lactic acid.

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Pancreatitis

Pancreatitis can be an acute complication of ART, even though it may occur after years of stable treatment.3 This potential fatal complication has been linked predominantly to the use of didanosine (ddI); however, stavudine (d4T) and lamivudine (3TC) have also been associated with pancreatitis. There may be an added potential for pancreatitis when using combinations of these nucleoside reverse transcriptase inhibitors (NRTIs). Importantly, the concomitant use of alcohol increases the risk of pancreatitis. In cases of acute pancreatitis, temporary interruption of ART is recommended. Subsequent resumption should avoid the likely causative agents the patient was taking at the time he or she developed pancreatitis.


Peripheral Neuropathy

Peripheral neuropathy usually occurs after prolonged use of NRTIs.4 This complication is most often associated with the use of the "d-drugs" -- zalcitabine (ddC), stavudine (d4T), and didanosine (ddI) (in decreasing order of likelihood). The combined use of two of these drugs has been associated with an even higher incidence of neuropathy. Recognizing neuropathic symptoms early on, and reducing or interrupting the offending agent(s) usually leads to symptom resolution. If patients are maintained on these drugs, progressive and often permanent neuropathy requiring narcotic analgesia may ensue.


Lactic Acidosis

Lactic acidosis syndrome (LAS) was first reported in the early 1990s in association with zidovudine (AZT) use, predominantly in obese African-American women. In recent years, the greatest association has been with the use of stavudine (d4T) with or without didanosine (ddI). The nucleoside and nucleotide analogues inhibit mitochondrial DNA production, which leads to an increased breakdown of fatty acids into lactic acid. Inhibition is greatest for the "d-drugs" but also occurs with the other NRTIs.5

Patients with LAS generally present with vague constitutional complaints including fatigue, malaise, abdominal pain, and nausea and vomiting. Over the course of several weeks, these patients can develop tachypnea, pancreatitis, and/or hepatitis in the setting of progressive acidemia. If unrecognized, death may occur. The clinician considering this diagnosis early on in the setting of vague complaints should obtain an arterial or venous lactate level. A mildly elevated level (2-5 mmol/L) is diagnostic of symptomatic hyperlactatemia, whereas a level >5 mmol/L in conjunction with a reduced arterial pH confirms the diagnosis of LAS. In both situations, interruption of ART until resolution is necessary. Subsequent therapy should, when possible, avoid those drugs most associated with LAS.


Metabolic Complications

Various metabolic complications associated with HIV have now been recognized. These include dyslipidemia, insulin resistance/diabetes (dysglycemia), and osteopenia/osteoporosis.


Dyslipidemia

Abnormal serum lipids have been noted since the beginning of the HIV epidemic. In the pre-ART era, patients commonly had hypocholesterolemia and hypertriglyceridemia as a function of their wasted hypercatabolic state, combined with increased pro-inflammatory cytokines.6 However, the highly active ART (HAART) era has been associated with a dyslipidemic profile consisting of high total and LDL cholesterols, elevated triglycerides, and a low HDL cholesterol. Although some patients may exhibit all three of these abnormalities, many will only have abnormalities in either the cholesterol or triglyceride fractions. The fraction most affected usually depends on the ARV agent(s) used (for example, ritonavir (RTV) predominantly affects triglycerides). The effect on lipids is most pronounced with protease inhibitors (PIs), followed by non-nucleoside and then nucleoside reverse transcriptase inhibitors.

The dyslipidemic profile is associated with an increased risk for atherogenesis, raising concern that as patients live longer due to HAART they may experience an increased risk for coronary or cerebral vascular morbidity and mortality.7 Multiple cohort studies comparing the frequency of coronary and/or cerebral vascular disease in HIV-infected patients with matched HIV-uninfected controls have shown an increased incidence of disease in those with HIV infection. Identification and management of individuals with dyslipidemia is now an essential part of HIV care. Guidelines are now available.8


Dysglycemia

Disorders of glucose metabolism, or dysglycemia, were one of the first metabolic complications of ART identified.9 Initial reports of new-onset hyperglycemia, including episodes of diabetic ketoacidosis, were linked to the use of protease inhibitors (PIs). Subsequent cohort studies have confirmed this association, which is largely due to acquired insulin resistance.10 Patients with HCV co-infection appear to be at greater risk of developing this complication.

Diagnosis is usually performed through periodic fasting glucose determinations or by a two-hour oral glucose tolerance test. Glycosylated hemoglobin levels are usually normal even in the setting of insulin resistance. Treatment depends on the severity of the hyperglycemia, with mild cases responding to dietary intervention and exercise, moderate cases responding to insulin-sensitizing agents such as the glitazones, and severe cases responding to insulin therapy. Modifying the regimen by replacing the PI with a non-PI agent may also be successful.


Disorders of Bone Metabolism

More recently, disorders of bone metabolism have been recognized as another long-term complication seen in HIV-infected patients.11 Osteopenia and osteoporosis have both been described in patients on ART, but predominately in those on HAART. The etiology of these changes has not been delineated, although there is a suggestion that the HIV-1 protease inhibitors may contribute to this process by affecting osteoclast or osteoblast differentiation. Diagnosis is made by standard DEXA scanning, although at this time routine DEXA scanning of all HIV patients is not indicated. However, for those with other risk factors for osteoporosis, such as family history, hypogonadism, smoking, and corticosteroid use, screening DEXA scanning should be considered. Preliminary studies have shown that alendronate is effective at treating osteoporosis in these patients.


Lipodystrophy

One of the most disconcerting toxicities increasingly recognized in the past three years is lipodystrophy, a disturbance in the way the body produces, uses, and distributes fat.12 Patients with long-term HIV infection, especially those treated with antiretroviral therapy, may exhibit changes in body morphology due to changes in fat distribution. Although these changes are usually not associated with medical complications, the disfigurement can be psychologically disabling.

Various cohort studies have estimated that up to 50% of patients suffer from lipodystrophy. Two patterns have emerged. Lipoatrophy, or subcutaneous fat loss, is seen most commonly in the face, extremities, and buttocks. Lipohypertrophy, or increased fat deposition, is seen predominantly in the abdominal region ("paunch"), dorsocervical region ("buffalo hump"), and breasts. Patients often have a combination of the two types of dysmorphic features.

The pathogenesis of fat maldistribution remains elusive. Retrospective cohort studies have defined characteristics associated with development of lipodystrophy: these include an age >40 years, nadir CD4 cell count, Caucasian race, and antiretroviral use. More recently, a prospective study of ARV-naive patients initiating therapy showed an association between development of lipoatrophy and use of a stavudine-containing regimen, and lipohypertrophy and the use of a PI-containing regimen. These investigators also defined a pattern to changes in body morphology occurring after initiation of therapy. Specifically, patients gained fat and lean mass during the first 24 weeks of therapy, followed by progressive loss of extremity fat while preserving gained central abdominal fat over the next 72 weeks of therapy.13

No definitive treatment for fat maldistribution exists, though different approaches have been tried. For lipoatrophy, several studies have shown that substitution of either zidovudine (AZT) or abacavir (ABC) for stavudine (d4T) may be associated with increases (albeit small) in subcutaneous fat, compared to continued declines in those remaining on stavudine (d4T). For lipohypertrophy, replacement of the protease inhibitor with a reverse transcriptase inhibitor may be useful.14

Cosmetic surgical options to treat facial lipoatrophy include a variety of methods of soft tissue augmentation. Although none of these procedures are specifically FDA-approved for this indication, some are FDA permissible as off-label use of approved agents. Bio-absorbale materials used for soft tissue augmentation include Zyplast collagen, human cadaveric dermal tissue (Cymetra), or fascia lata (Fascian) polylactic acid (New-Fill), hyaluronic acid (Perlane) and fat transfers. Permanent options include implants, liquid injectable medical grade silicone (Silikon-1000), and polymethylmethacrylate (Artecoll).

For buffalo humps that cause disfigurement, neck pain, or sleep apnea, liposuction may be effective. Human growth hormone has also been shown to decrease buffalo hump and excess abdominal fat.15 However, high cost and tolerability issues have led few patients to use this approach. Once ongoing research establishes the definitive cause of fat maldistribution, more specific therapeutic options can be developed.


Hepatotoxicity Unrelated to Chronic Viral Hepatitis

Previous articles in HEPP Report have extensively covered the effects of chronic HBV and HCV in patients with HIV (go to www.hivcorrections.org). However, hepatotoxicity occurs in HIV-infected patients even in the absence of chronic viral hepatitis. Some of these are acute drug toxicities, such as those seen with hypersensitivity to nevirapine (NVP). One under-recognized toxicity is non-alcoholic steatohepatitis (NASH). NASH may be seen in HIV-uninfected patients and is usually associated with obesity, diabetes, or certain medications, and can progress to cirrhosis if untreated. In HIV-infected patients, NASH has been reported to occur in those with prolonged hypertriglyceridemia and insulin resistance, usually secondary to HAART. These patients present with sustained, mild-to-moderate elevations in serum transaminases (AST or ALT) with no serologic or virologic evidence of chronic HBV or HCV infection. Hepatic ultrasound or CT scan will show a pattern consistent with fatty liver. Liver biopsy will show steatosis with or without fibrosis or cirrhosis. Treatment involves therapy for the hypertriglyceridemia or insulin resistance, abstinence from any alcohol intake, use of antioxidants such as vitamins C and E, and in some cases alteration of the current ARV therapy to remove the agents contributing to hypertriglyceridemia or insulin resistance.16


Conclusion

The ART era has been a miraculous time for many patients with HIV infection and for those providing care. For patients with access to ARV therapy, HIV/AIDS has the potential to become a manageable, chronic disease. However, there are many prices to pay for this, including a lifetime need for complex medical regimens associated with acute toxicities. In the last few years, we have learned that there are chronic complications of both ARV therapy and prolonged survival with HIV infection. Some of these complications can be immediately life-threatening, whereas others have implications for patients' future morbidity and mortality. In either case, patients and health care providers must recognize that these long-term complications exist. Importantly, health care providers need to understand how to diagnose and manage these complications in order to provide optimal long-term care to their patients with HIV infection.


Suggested Reading
M Schambelan, et al. Management of Metabolic Complications Associated With Antiretroviral Therapy for HIV-1 Infection: Recommendations of an International AIDS Society-USA Panel. JAIDS 2002, 31: 257-75.


Peter J. Piliero, M.D. is Associate Professor of Medicine at Albany Medical College. Disclosures: Abbott (honoraria, consultant); Roche, Merck, GlaxoSmithKline, BMS (honoraria, research funding).


References

  1. Max B, Sherer R. Management of the adverse effects of antiretroviral therapy and medication adherence. Clin Infect Dis 2000; 30 (Suppl 2): S96-116.

  2. Shikuma CM, Shiramizu B. Mitochondrial toxicity associated with nucleoside reverse transcriptase inhibitor therapy. Current Inf Dis Reports 2001; 3: 553-560.

  3. Dassopoulos T, Ehrenpreis ED. Acute pancreatitis in HIV-infected patients: A review. Am J Med 1999; 107: 78-84.

  4. Simpson DM, Tagliati M. Nucleoside analogue-associated peripheral neuropathy in HIV infection. J Acquir Immune Defic Syndr 1995; 9: 153-161.

  5. Gerard Y, Maulin L, Yazdanpanah Y, et al. Symptomatic lactatemia: an emerging complication of antiretroviral therapy. AIDS 2000; 14: 2723-2730.

  6. Grunfeld C, Kotler DP, Hamadeh, et al. Hypertriglyceridemia in the acquired immunodeficiency syndrome. Am J Med 1989; 86: 27-31.

  7. Stein JH. Dyslipidemia in the era of HIV protease inhibitors. Prog Cardiovasc Dise 2003 Jan-Feb. 293-304.

  8. Dube MP, Sprecher D, Henry WK. Preliminary guidelines for the evaluation and management of dyslipidemia in adults infected with human immunodeficiency virus and receiving antiretroviral therapy: Recommendation of the Adult AIDS Clinical Trials Group Cardiovascular Disease Focus. Clin Infect Dis 2000; 31: 1216-1224.

  9. FDA. FDA Medical Bulletin 1997; 27(2).

  10. Hadigan C, Meigs JB, Corcoran C, et al. Metabolic abnormalities and cardiovascular disease risk factors in adults with HIV infection and lipodystrophy. Clin Infect Dis 2001; 32: 130-139.

  11. Mondy K, Yarasheski K, Powderly WG, et al. Longitudinal evolution of bone mineral density and bone markers in HIV-infected individuals. Clin Infect Dis 2003; 36: 482-490.

  12. Lichtenstein K, Armon C, Moorman A, et al. Clinical assessment of HIV-associated lipodystrophy in an ambulatory population. AIDS 2001; 15: 1389-98.

  13. Mallon PW, Miller J, Cooper DA, Carr A. Prospective evaluation of the effects of antiretroviral therapy on body composition in HIV-1-infected men starting therapy. AIDS. 2003 May 2;17(7):971-9.

  14. Saag MS, Powderly WG, Schambelan M, et al. Switching antiretroviral drugs for treatment of metabolic complications in HIV-1 infection: summary of selected trials. Topics HIV Med 2002; 10:47-51.

  15. Kotler D, Thompson M, Grunfeld C, et al. Growth hormone effectively reduces visceral adipose tissue accumulation and non-HDL cholesterol. XIV International AIDS Conference 2002, Barcelona; LbOR18.

  16. Tien PC, Grunfeld C. The fatty liver in AIDS. Semin Gastrointest Dis 2002; 13(1): 47-54.


Back to the HEPP Report June 2003 contents page.

A note from TheBody.com: Since this article was written, the HIV pandemic has changed, as has our understanding of HIV/AIDS and its treatment. As a result, parts of this article may be outdated. Please keep this in mind, and be sure to visit other parts of our site for more recent information!



  
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This article was provided by Brown Medical School. It is a part of the publication HEPP Report.
 
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