- Side Effects and Toxicities Associated with Anti-HIV Drugs
Drug Interaction Studies
Ortho-Novum 1/35 (oral contraceptive pill) and nevirapine
G. Leitz, MD, and Donna Mildvan, MD, of Beth Israel Medical Center in New York reported that oral contraceptives "should not be used as the primary means of contraception when [nevirapine] is prescribed to HIV-infected women of child-bearing potential." Nevirapine significantly decreased blood hormone levels of Ortho-Novum 1/35. The progestin component, norethindrone, had an 18% median reduction in the AUC concentration. The estrogen component, ethinyl estradiol, had a 29% median reduction in the AUC concentration. In addition, the researchers found that the half-life of ethinyl estradiol decreased by over four hours. Ortho-Novum 1/35 did not affect plasma levels of nevirapine. Fourteen HIV positive women (86% African-American, 14% Latina) were enrolled and ten completed the one-month study. Blood levels of ethinyl estradiol also are significantly decreased when the drug is combined with the PIs nelfinavir or ritonavir. However, levels of both ethinyl estradiol and
norethindrone are increased by approximately 25% when taken with the PI indinavir. No dose adjustment is recommended when Ortho-Novum 1/35 is combined with indinavir.
Saquinavir plus ritonavir and drugs used to reduce high cholesterol
Some very interesting drug interaction studies about drugs used to treat high blood levels of cholesterol were presented. When saquinavir 400 mg plus ritonavir 400 mg are taken, treating high blood cholesterol with pravastatin (Pravachol) is safe. (If pravastatin does not reduce the cholesterol level, the dose may need to be increased.) Simvastatin (Zocor) should not be used in this context, however, and atorvastatin (Lipitor) should be used with caution. If any toxicity results from atorvastatin, the dose may need to be reduced. In this study, simvastatin blood levels increased by 2,676% (approximately 27-fold), atorvastatin levels increased by 74%, and pravastatin levels decreased by 47%. Evaluation of saquinavir and ritonavir levels with each of the three cholesterol-lowering drugs is still in progress. The study enrolled 52 healthy HIV negative volunteers. The report was authored by C. Fichtenbaum, MD, of the University of Cincinnati.
Methadone dosing with efavirenz, nevirapine, or nelfinavir
The dosing of methadone with either efavirenz or nevirapine may need to be increased starting seven days after either NNRTI is begun. S. Clark, MD, and colleagues from St. James’s Hospital in Dublin, Ireland, and the Department of Pharmacology and Therapeutics in Liverpool, UK, presented their recommendations. They reported that methadone dosing "may need to be increased in increments of 10 mg from day 7-10 onward [after starting an NNRTI drug regimen], using clinical symptoms and signs to assess requirements." Nineteen persons had detailed pharmacokinetic studies done with either efavirenz or nevirapine. In this group, 89% had "symptoms consistent with methadone withdrawal from day 7-10 onward." The symptoms required methadone to be increased by a mean of 22%, corresponding to 16 mg, with a range of 15-30 mg.
The researchers also commented that since neurological symptoms between days 1-5 may appear to be opiate withdrawal, for those who are taking efavirenz, a "careful evaluation and clinical assessment" should differentiate between withdrawal and efavirenz side effects. When either efavirenz or nevirapine is stopped due to toxicity or viral rebound, opiate intoxication would be the opposite problem. In that setting, the dose of methadone should be "gradually reduced over a 2-3 week period to the pretreatment dose." Methadone is a long-acting oral opiate drug taken by former heroin users who seek to avoid injection drug use.
A separate report about methadone and nelfinavir was authored by Poe-Hirr Hsyu, PhD, of Agouron Pharmaceuticals. Dr. Hsyu reported results of a prospective study of 14 HIV positive persons on chronic methadone maintenance at a dose of 10-140 mg daily. Nelfinavir 1,250 mg twice daily was then added. This led to decreased blood levels of methadone and its metabolites (breakdown products) by one-third to one-half. However, none of the subjects developed opiate withdrawal symptoms during the study. In a separate retrospective analysis of 36 HIV positive subjects who were taking 20-110 mg of methadone daily, adding nelfinavir (1,250 mg twice daily or 750 mg three times daily) led to a necessary dose modification of methadone in two of them (6%). The period of observation ranged from 3-105 weeks.
Rifabutin (Mycobutin) and PI interactions
Research was presented that examined the drug interaction of the antibiotic rifabutin and either indinavir or hard gel saquinavir (Invirase) plus ritonavir.
Dr. F. Hamzeh and colleagues from Johns Hopkins University in Baltimore were the authors. Mycobutin is used to treat and prevent Mycobacterium infections, including Mycobacterium avium complex (MAC) and Mycobacterium tuberculosis (TB), two life-threatening OIs. Previously, it was recommended that rifabutin should not be combined with indinavir, due to resulting low blood levels of the PI. When combined with rifabutin 150 mg once daily, a dose of indinavir 1,000 mg every eight hours led to blood levels of indinavir similar to those that occur when it is taken at the standard dose (800 mg) every eight hours without rifabutin. Blood levels of rifabutin are still being evaluated. Until these results are reported, the revised dosing cannot be recommended.
Another report was presented by Keith Gallicano, PhD, of Ottawa General Hospital in Ontario, Canada. Dr. Gallicano addressed combining rifabutin with the double combination of hard-gel saquinavir plus ritonavir. He found that a rifabutin dose of 300 mg once weekly or 150 mg every three days with 400 mg twice daily of both hard gel saquinavir and ritonavir represents "a safe and manageable regimen for concurrent therapy" of all three drugs. Nineteen HIV positive persons (16% women) completed the eight-week study. Maximal and AUC concentrations of saquinavir and ritonavir increased insignificantly. In comparing rifabutin blood levels without concurrent PIs, the authors reported that the decreased AUC of rifabutin was essentially balanced by the increased AUC of the active rifabutin metabolite (breakdown product called desacetyl rifabutin) in the 300 mg weekly dosing arm. These results provide another option for HIV positive persons taking these PIs who also have TB or MAC
that requires treatment.
Combining amprenavir or saquinavir with efavirenz
New research has found that lowered drug levels of amprenavir or soft-gel saquinavir due to efavirenz can be avoided by adding ritonavir in a twice-daily dose of 200 or 400 mg, respectively. Previously, studies had shown that the blood levels of either amprenavir or saquinavir were significantly decreased by coadministration of efavirenz. This meant that the dose of either PI had to be increased when combined with standard dosing of efavirenz. Now, researchers from Johns Hopkins University have determined that when ritonavir is added as a second PI to either dual combination, the negative interaction is avoided. In both of these studies, the standard efavirenz dosing of 600 mg once daily was used. In the study of amprenavir/ritonavir/efavirenz, the ritonavir dose was 200 mg twice daily. Interestingly, adding that dose of ritonavir to standard amprenavir dosing of 1,200 mg twice daily increased the minimum amprenavir concentration by 5-fold, while the AUC concentration was
increased by more than 2-fold. Blood levels of neither efavirenz nor ritonavir were reported. In the study with saquinavir/ritonavir/efavirenz, the dosing of the first two drugs was 400 mg twice daily. In that study, ritonavir and efavirenz blood levels showed an insignificant decrease or no change.
Saquinavir and ritonavir dosing should not be staggered
These two PIs should be taken at the same time, not several hours apart, according to Dr. T. Blaschke and colleagues from Stanford University in Palo Alto, CA. The AUC concentration of saquinavir decreased 63% when it was taken four hours before ritonavir.
Combining two NNRTIs
According to A.I. Veldkamp, MD, and colleagues from Slotervaart Hospital in the Netherlands, combining nevirapine with efavirenz led to drug levels that were too low for efavirenz, while nevirapine levels were unchanged. Both drugs are NNRTIs. Dr. Veldkamp recommended that the daily dose of efavirenz be increased to 800 mg. According to Charles Hicks, MD, of Duke University in Durham, NC, when emivirine (Coactinon, an experimental NNRTI) was combined with efavirenz, blood levels were too high for emivirine and too low for efavirenz. In that example, Dr. Hicks also recommended the same efavirenz dosing increase, while decreasing the emivirine dose to 500 mg twice daily. Dr. Hicks added that monitoring plasma levels of the anti-HIV drugs will be necessary. In the past, the only anti-HIV drug combinations that contained two NNRTIs were experimental "mega-HAART" salvage regimens, which included five or more anti-HIV drugs.
Side Effects and Toxicities Associated with Anti-HIV Drugs
High cholesterol from ritonavir in HIV negative volunteers
According to Kathleen Mulligan, PhD, of San Francisco General Hospital, two weeks of taking ritonavir caused increased cholesterol and triglycerides even in HIV negative volunteers. Dyslipidemia (abnormal blood fats) has occurred to varying degrees in HIV positive persons who take a PI or efavirenz.
Is it possible to predict an NNRTI allergic rash?
Maria DeRisi, PharmD, of the University of California at San Diego (UCSD) presented some interesting findings about predicting an allergic rash from NNRTIs. Four hundred and thirty-six persons who had previously taken an NNRTI were included in this retrospective study. Latinos had an overall 20% risk (2.6-fold increased odds ratio) of developing an NNRTI rash, when compared with any other race/ethnicity. For all persons, a history of a sulfa rash increased the risk of an NNRTI rash to 28% (one in four chance, or 8-fold increased odds ratio). (Sulfa antibiotics [Bactrim, Septra] are used to treat or prevent PCP.) If someone had previously taken a sulfa antibiotic and did not have a rash, the risk of a rash after taking an NNRTI was only 5%. Without any history of a sulfa rash, the overall rate in Blacks was 6%, and 10% in Whites. Each of the following factors was not significantly associated with an increased risk of a rash: baseline CD4 cell count, gender, and specific type of
NNRTI. This information should be useful for persons with HIV and their physicians in choosing an anti-HIV regimen. An allergic rash is a common side effect in the NNRTI drug class, but usually does not require stopping the drug. Life-threatening rashes may occur very rarely.
Toxicity to mitochondria in cells
Previously, Kees Brinkman, MD, of Amsterdam has put forth his hypothesis about some of the newer side effects from anti-HIV drugs resulting from their toxicity to cellular mitochondria (energy producers within cells). Specifically, he has referred to the nucleotide reverse transcriptase inhibitor class. David Cooper, MD, DSc, of the University of New South Wales, Australia, discussed the possible role of mitochondrial damage in the syndrome known as lipodystrophy (abnormal fat redistribution). Unfortunately, there are many unanswered questions in this area, and association does not necessarily mean causation. It has been shown previously that several toxicities of the nucleotide reverse transcriptase inhibitor drug class result from mitochondrial damage, including myopathy (muscle disease), neuropathy (nerve disease), pancreatitis (inflammation of the pancreas), and liver failure. Mitochondrial disease in HIV negative adults rarely is associated with multiple symmetric
lipomatosis, a disease of fatty growths (lipomas) under the skin, somewhat similar to the "buffalo hump" that can develop over the base of the neck in HIV positive adults receiving anti-HIV therapy.
Animal models to help understand side effects
(Note that laboratory animal models are helpful in understanding drug side effects, but the results do not always predict what happens in humans.) Genetic susceptibility to obesity and dietary factors (e.g., fat intake) should be considered when evaluating the role of anti-HIV drugs in body fat redistribution and metabolic changes, according to James Lenhard, PhD, of Glaxo Wellcome. Dr. Lenhard reported that when inbred mice genetically susceptible to diet-induced obesity were fed a high-fat diet, taking indinavir or nelfinavir led to much higher blood triglyceride levels than either saquinavir or amprenavir did. Using concentrations similar to those used for humans, Dr. Lenhard also showed that efavirenz use did lead to significantly increased blood triglycerides in the same mice genetically prone to obesity. In addition, there was a trend towards increased cholesterol levels. (Previously, studies have shown that efavirenz induces an increase in the HDL cholesterol, high density
lipoprotein or "good" cholesterol.) In a laboratory liver cell model, Dr. D. Winegar, also of Glaxo Wellcome, reported that ritonavir and nelfinavir both stimulate production of triglycerides from these cells. In contrast, using saquinavir, indinavir, or amprenavir did not lead to triglyceride production.
Other selected findings about anti-HIV drug side effects and fat redistribution
- There still is no case definition of lipodystrophy syndrome.
- Fat redistribution appears to be more likely related to duration of anti-HIV therapy, rather than duration of HIV infection. This is based upon a report by J. Miro, MD, of the University of Barcelona who found that fat redistribution occurred among one-third of persons who had been taking HAART for up to two years after starting during primary, or acute, HIV infection (severe flu-like illness).
- Results from the Self Ascertained Lipodystrophy Syndrome Assessment (SALSA) study indicated a very high prevalence rate of fat redistribution that was different when comparing men with women. According to Dr. N. Muurahainen of Betances Health Unit in New York, fat accumulation was present in 84% of men and 97% of women, whereas fat loss was present in 77% of men and 61% of women.
- Fat redistribution may have different prevalence rates among different racial/ethnic groups. According to Dr. S. Raghavan and colleagues from Harlem Hospital Center in New York, a lower rate of fat redistribution was present in African-American and Latino HIV positive persons than in historical reports of Whites. Their retrospective study analyzed 130 persons (39% women, 85% African-American, and 15% Latino).
- Low bone mineral density (osteopenia, osteoporosis, "thin bones") might be another complication of PI therapy, according to two separate reports showing a 28% and 38% prevalence rate, respectively. The lead authors were Jennifer Hoy, MD, of Alfred Hospital in Melbourne, Australia, and Pablo Tebas, MD, of Washington University in St. Louis.