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Published in the Bulletin of Experimental Treatments for AIDS January 1999 issue, by the San Francisco AIDS Foundation.
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Highlights from Recent Conferences -- Protease Inhibitor Complications And Side EffectsHarvey S. Bartnof, MD HAART Increases Shingles Rate
HAART has been associated with acute conditions related to immune response restoration within a few weeks to months of starting treatment (see "Opportunistic Infections", this issue). Now, two different research groups have reported another such condition: shingles (herpes zoster). Shingles is characterized by a painful rash of blisters, and is due to a reactivation of the varicella-zoster virus). The first report was from St. George’s Hospital in London. Researchers found that the rate of shingles among their HIV positive patients increased five-fold after HAART was initiated. The mean time to the development of shingles was 16 weeks after starting or switching to HAART. Moreover, the researchers noted that 50% of their patients developed shingles within four weeks after starting or switching to HAART. The previous shingles rate in this population was not stated in the abstract, nor was the number taking preventive therapy for herpesvirus infections. The second report was from the Unidad VIH Hospital Clinico de San Carlos in Madrid. The authors described thirteen persons who had a reactivation of herpes zoster infection after a mean of three and one-half months of HAART (the previous study did not state whether the cases were first episodes or reactivations). Specific rates were not calculated, but the researchers concluded that "herpes zoster reactivation may be an immune recovery disease." It is striking that there were two separate reports of herpes zoster occurring within nearly identical time frames after starting HAART. If high shingles rates after starting HAART are also seen in other populations, there may be a benefit to taking herpes prophylaxis therapy within the first one to four months after starting potent antiretroviral therapy. Such preventive therapy could include acyclovir (Zovirax) or famciclovir (Famvir). Estrada, V. and others. Herpes zoster reactivation soon after beginning HAART: and indicative of immune recovery. 4th ICDTHI. Abstract P294. Lau, R. and others. Herpes zoster infection in HIV-seropositive patients associated with highly-active antiretroviral treatment. 4th ICDTHI. Abstract P282. HAART May Increase Rate of WartsResearchers at the University of California at San Francisco (UCSF) have noted an increase in the rate of warts among their HIV/AIDS patients. Deborah Greenspan, BDS, and colleagues measured the rates of various HIV-related conditions in the mouth before and after the introduction of HAART. The study population was the Women’s Interagency HIV Study (WIHS). The only condition for which there was an increase after HAART was oral warts. Greenspan stated that she has also noted a similar increase in warts among men with HIV/AIDS, although specific rate measurements have not been done. The rates of many other oral conditions have decreased, including oral candidiasis and hairy leukoplakia. A similar trend was reported by Toby Maurer, MD, of the Department of Dermatology at San Francisco General Hospital. Maurer reported that the rate of skin warts had increased markedly since HAART became available. She noted that warts are generally not nearly as much of a problem after the CD4 count increases to greater than 400 cells/mm3. Maurer also noted that allergic reactions to antibiotic drugs and eosinophilic folliculitis (inflammation of the hair follicles) have both increased since the advent of HAART. Maurer indicated that rates of other skin conditions have decreased, including Kaposi’s sarcoma and molluscum contagiosum. There have also been anecdotal reports from other institutions indicating increased rates of warts among HIV positive persons taking HAART. The exact mechanism for the increase is not known. It is likely associated with an improved immune response, and is possibly related to altered cytokine levels. Another hypothesis is that as people with HIV are living longer due to HAART, the rate of warts is increasing. Greenspan, D. Oral disease in HIV. Comprehensive Review of HIV Management, University of California at San Francisco. December 10-12, 1998. Maurer, T. HIV dermatology in these changing times. Comprehensive Review of HIV Management, University of California at San Francisco. December 10-12, 1998. High Blood Lipids Respond to Gemfibrozil and/or Atorvastatin
One side effect associated with protease inhibitor therapy is increased blood levels of fats, including triglycerides and cholesterol. An increase in the former raises the risk of life-threatening pancreatitis (inflammation of the pancreas, a digestive system organ), which has occurred rarely in HIV positive persons taking a protease inhibitor. An increase in low density lipoprotein (LDL) "bad" cholesterol increases the risk of heart attack and angina (chest pain due to decreased blood supply to the heart), and there have been reports of heart attacks in people taking HAART (see BETA, October 1998). Increases in blood fat levels in people taking HAART are often treated by physicians, but previously there had been no published reports of the efficacy of such treatment. Now, R.G. Hewitt, MD, and colleagues from the State University of New York at Buffalo have reported benefits from treating high triglyceride levels with gemfibrozil. The physicians described treatment of eight HIV-positive men. Among the eight men, all four protease inhibitors were represented. Before initiating gemfibrozil treatment, triglyceride levels had increased from a median baseline of 298 milligrams per deciliter (mg/dL) to a very high median of 1,803 mg/dL; these increases occurred after 41-394 days of protease inhibitor therapy. After an average of three months of gemfibrozil therapy, the median lowest triglyceride level was 300 mg/dL, representing a significant 83% reduction. There were no significant changes in blood cholesterol levels. One man temporarily stopped gemfibrozil therapy, and his triglyceride level increased. When the treatment was restarted, his triglyceride level decreased again. Interestingly, five of the eight men had their protease inhibitor switched to nelfinavir while taking gemfibrozil. This caused an increase in triglyceride levels from a median low of 230 mg/dL to 611 mg/dL. The authors believe that this occurred due to an adverse drug interaction. A second report regarding the treatment of high blood fats associated with protease inhibitor therapy was published in the September 26, 1998 issue of The Lancet. Keith Henry, MD, and colleagues reported using gemfibrozil and, if necessary, atorvastatin. There were 133 patients in the physicians’ HIV clinic who were taking protease inhibitors. Of that group, 44 had high blood fats according to National Cholesterol Education Program (NCEP) guidelines while taking antiretroviral therapy. Pre-protease inhibitor blood lipid levels were not known for everyone, thus the change associated with HAART could not be determined for some patients. The rates of high blood fat levels associated with each protease inhibitor were 66% for ritonavir/saquinavir, 32% for indinavir, and 39% for nelfinavir. Medical histories of cardiovascular risk factors were obtained, including smoking, high blood pressure, diabetes, family history, diet, and exercise. All patients received counseling regarding the benefits of diet and exercise. Some had blood fat levels that responded to these interventions alone. However, 25 patients required gemfibrozil, and 29 were started on atorvastatin. Among those 54 persons, 19 were eventually given both drugs, due to a mediocre response to either drug alone. After an average of six months, those 19 had a mean 30% decrease in cholesterol level and a mean 60% decrease in triglyceride level. The mean levels of each were still abnormally high, but were not nearly as high as before lipid-reducing therapy was started. In HIV negative persons, gemfibrozil increases high-density lipoprotein (HDL) "good" cholesterol and decreases triglycerides. Conditions which usually preclude therapy with this drug include liver and kidney abnormalities and gall bladder disease. Side effects include abdominal cramps, intestinal gas, nausea, dizziness, fatigue, muscle aches, and rash. Abnormal laboratory tests resulting from the drug include increased liver function tests and blood cell toxicities. Atorvastatin is one of the potent "statin" drugs that help treat high blood fat levels. In HIV negative persons, it has been shown to decrease high levels of total blood cholesterol, LDL cholesterol, and triglycerides; it also increases HDL cholesterol levels. The drug works by inhibiting the production of sterol, a precursor to cholesterol. Atorvastatin can cause liver and muscle toxicity, and should not be taken by patients with chronic liver disease, or by women who are pregnant or breast-feeding. Side effects include abdominal cramps, diarrhea, muscle aches, and weakness. Henry K. and others. Atorvastatin and gemfibrozil for protease-inhibitor-related lipid abnormalities. The Lancet 352:1031-1032. September 26, 1998. Hewitt, R.G. and others. Gemfibrozil effectively lowers protease inhibitor-associated hypertriglyceridemia in HIV-1 + patients. 38th ICAAC. Abstract I-88. Hip Bone Death and HAART
C. Gaultier, MD, and colleagues from Los Angeles reported on three cases of hip bone cell death (avascular necrosis) potentially related to high blood fat levels associated with HAART. This hip condition starts with pain that increases with standing or walking. All three cases were men in their forties who required hip replacement surgery. All were taking four-drug HAART regimens. Two were taking double protease inhibitor therapy (ritonavir/saquinavir), while the third was taking indinavir. All three had undetectable HIV viral loads (limit of quantitation not stated), with a mean CD4 cell count of 308 cells/mm3. All three also had high fasting blood fat levels, and two had blood cholesterol levels over 325 mg/dL (a normal level is less than 200 mg/dL). None of the men had any known risk factors for hip disease, including diabetes, hip injury, arthritis, radiation exposure, or recent therapy with megestrol acetate (Megace) or steroids. The authors believe that the increased blood fats subsequent to HAART may have been a co-factor in the development of avascular hip necrosis in these men. This author is aware of at least one other case of the same problem possibly associated with HAART. A retrospective analysis using HIV/AIDS patient cohorts could help to determine whether this association is real or merely coincidental. Gaulter, C. and others. Incidence of avascular necrosis of the hip in HIV-infected individuals on HAART. 38th ICAAC. Abstract I-71. Cushing’s Syndrome from Ritonavir plus FluticasoneThe adrenal glands on top of each kidney produce steroid hormones that are required for normal body functioning. Excess levels of these hormones can lead to a constellation of symptoms called Cushing’s syndrome, characterized by a round face, a dorsocervical fat pad ("buffalo hump") on the upper part of the back, and weight gain. The buffalo hump that is seen in some people taking protease inhibitors is not associated with Cushing’s syndrome (see BETA, January 1998). Now, for the first time, Cushing’s syndrome has been reported in an HIV positive man who was taking ritonavir (600 mg twice daily) plus AZT/3TC. The man was also chronically using fluticasone (Flonase), a steroid nasal spray. The spray is used to treat nasal allergies and is also sometimes used as an adjunct to antibiotic drugs when treating a sinus infection. Usually, very little of the drug is found in the bloodstream due to metabolic breakdown by the liver. The man denied taking or using any other steroid preparations. Signs of Cushing's syndrome began to appear in the man after two months of anti-HIV therapy. The report's authors believe that inhibition of the liver's CP450 enzyme system by ritonavir blocked the normal breakdown of fluticasone. This in turn caused fluticasone to accumulate in the bloodstream, leading to Cushing’s syndrome. Additional tests of the man's adrenal gland function revealed no production of any natural steroid hormone, due to the excess from fluticasone. The patient’s Cushing's syndrome symptoms resolved when the nasal spray was discontinued. People with HIV and their physicians should be aware of the potential complications that may result from simultaneous use of ritonavir and fluticasone. Chen, F. and others. Severe adrenal suppression in a patient treated with ritonavir and nasal fluticasone. 4th ICDTHI. Abstract P159. Breast Enlargement in MenWhile significant breast enlargement has been reported in HIV positive women taking protease inhibitor therapy (see BETA, October 1998), the occurrence of breast enlargement in men had not been fully appreciated. Now, researchers have reported breast enlargement in three HIV positive heterosexual men from Greece who were taking HAART that included saquinavir. The men noted painful swelling in the breast area. The enlargement began after one year of HAART. The men's breasts had an appearance similar to that of female breasts. Ultrasound and mammography tests indicated an increase in mammary gland tissue in both breasts. The men denied taking any hormone therapy, specifically female hormones. A full panel of endocrine blood tests was normal. A similar case report of breast enlargement in an HIV infected bisexual man was published in a recent issue of AIDS. The man was treated with ritonavir and saquinavir (400 mg each twice daily) plus AZT and 3TC. After three months, ritonavir was stopped due to intolerance, and saquinavir was increased to 600 mg three times daily. After five more months, the saquinavir was switched to standard dose nelfinavir. After a total of 11 months of protease inhibitor therapy, the man began noticing enlarged breasts that had a female appearance. True gynecomastia (female-appearing excessive breast development in men) was confirmed by ultrasound and mammography tests. A full hormone evaluation was normal. Other causes of enlarged breasts were not present, including liver disease, alcoholism, and supplemental hormone therapy. The man was taken off protease inhibitor therapy and his regimen was changed to nevirapine/ddI/d4T. However, seven months later, there was no change in the appearance of his breasts. The authors note that the patient became considerably depressed after the breast enlargement occurred. He stated that he "would not have started treatment so early if he had known about the risks." Notably, the man did not have any increases in blood fat levels, including cholesterol or triglycerides, while taking protease inhibitors. Breast enlargement is one component of the abnormal fat redistribution syndrome that can occur in those taking protease inhibitor therapy. The true rate of this occurrence among men taking protease inhibitors is not known. However, even if it is rare, for many men the possibility of this side effect might tip the scale in the direction of deferring protease inhibitor therapy. Lioni, A. and others. True gynecomastia and not adipose tissue deposition in 3 HIV(+) patients under triple antiretroviral regimen: an unknown adverse effect? 4th ICDTHI. Abstract P160. Schurmann, D. and others. Gynaecomastia in a male patient during protease inhibitor treatment for acute HIV disease. AIDS 12(16):2232-2233. 1998. Bleeding in Hemophiliacs
Ruiz, I. and others. Bleeding in hemophilic patients on protease inhibitors. 4th ICDTHI. Abstract P155. Clubfoot: Another Birth Defect Related to HAART?Potential birth defects associated with the newer anti-HIV therapies are unknown. At the 12th World AIDS Conference in June 1998, premature births, infant brain hemorrhage, and a bile duct malformation were described as possible adverse effects in newborns whose mother took HAART. Now, researchers from Brazil have reported a clubfoot defect in both feet of a full-term newborn whose mother took indinavir/AZT/ddI from the fourth through ninth months of pregnancy. The mother denied taking any other drugs during pregnancy. There were no other risks for congenital clubfoot, including radiation exposure or family history of any birth defects. The occurrence could be a coincidence, or it could possibly be due to HAART. Only future similar reports -- or the lack thereof -- will reveal the answer. Souza. E, and other. Talipes equinovarus (clubfoot) in an HIV exposed newborn whose mother used HAART: possible role of triple therapy. 4th ICDTHI. Abstract P89. Next section of highlights from
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