Long-Term Toxicities Associated With HIV and Antiretroviral Therapy
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
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.
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.
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.
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.
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
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.
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.
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.
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
This article was provided by Brown Medical School. It is a part of the publication HEPP Report.