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HIV Entry Inhibitors Stuck in the Pipeline

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HIV Entry Inhibitors Stuck in the Pipeline January 15, 2006 • www.familypracticenews.com Infectious Diseases 41 HIV Entry Inhibitors C LINICAL G UIDELINES F OR F AMILY P HYSICIANS Stuck in the Pipeline Nonoccupational Postexposure HIV Prophylaxis BY NEIL S. SKOLNIK, M.D., AND JINN LIU, M.D. BY ROBERT FINN age the earlier emergence of X4 San Francisco Bureau viruses. Indeed, this apparently hap- n 1998, the Department of Health and Hu- drug HAART regimen are based on the as- pened in five or six patients in the man Services concluded there was insuffi- sumption that maximal suppression of viral S AN F RANCISCO — Efforts to clinical trials, Dr. Deeks said, and Icient evidence to recommend for or against replication will provide the best chance for develop entry inhibitors, which this is likely to be associated with nonoccupational postexposure HIV prophylax- preventing infection. constitute the first new class of more rapid disease progression. is. Since that time, data from studies on nonoc- anti-HIV drugs in years, have hit The difficulties that aplaviroc, vi- cupational postexposure prophylaxis (nPEP) Other Considerations snags that could delay the entry of criviroc, and maraviroc have run have accumulated, and the guidelines have been Adherence to antiretroviral medications is these novel agents into the phar- into are not related to this, howev- updated (MMWR Recomm. Rep. 2005;54:1-20). challenging. Common side effects include maceutical marketplace. er. Aplaviroc has been associated nausea and fatigue, and each The debut of entry inhibitors with five cases of liver toxicity, all of The Evidence dose reminds the patient of has been eagerly awaited because which involved a threefold increase The CDC guidelines are sup- Guidelines are most useful his or her risk for acquiring of preclinical hints that they may in ALT and a 1.5-fold increase in ported by many studies. In when they are available at the HIV infection. be highly effective and have few bilirubin. In all cases, this elevation one such study, 700 patients point of care. A concise yet Patients seeking care after side effects. But all three entry in- in enzymes declined when the drug were evaluated 12 weeks af- complete handheld computer HIV exposure should be test- hibitors in clinical trials have run was removed, and in the one case ter nPEP initiation; 7 of the version of this guideline is ed for HIV antibodies at base- into difficulty, and one has now in which the patient was rechal- individuals seroconverted. Of available for download, line, 4-6 weeks, 3 months, and been withdrawn from develop- lenged with aplaviroc, the liver tox- those seven, three reported compliments of FAMILY 6 months after treatment ini- ment, Dr. Steven W. Deeks said at icity recurred. Further development high-risk behavior after start- PRACTICE NEWS, at tiation to determine HIV se- a meeting on HIV management of aplaviroc has been stopped. ing nPEP, so the seroconver- www.redi-reference.com. roconversion. Testing for sex- sponsored by the University of There was hope that entry in- sion in these patients may ually transmitted diseases, California, San Francisco. hibitors might be a good first-line not be entirely due to med- hepatitis B and C, and preg- GlaxoSmithKline therapy in treat- ication failure. nancy should also be offered. In patients under- has discontinued its Aplaviroc has ment-naive patients. In studies of mother-to-child HIV transmis- going nPEP, liver function, renal function, and development of been associated But a study com- sion, additional benefit appeared to occur when hematologic parameters should be monitored. Aplaviroc, which ap- paring Combivir the neonate received prophylaxis in addition to If possible, the source should be interviewed pears to have caused with five cases of plus efavirenz with reducing maternal viral load around delivery. to determine the history of antiretroviral use at least five cases of liver toxicity, all Combivir plus vi- A study of sexual assault survivors in Brazil and most recent viral load. This information liver toxicity. Scher- criviroc in patients showed zero seroconversions in the 180 nPEP- may be useful when choosing nPEP medica- ing-Plough’s vicrivi- of which involved who were treatment treated women compared with four serocon- tions. The risk for transmission might be es- roc did not perform a threefold naive was terminat- versions in the untreated group of 145 women. pecially great if the source has been infected as well as efavirenz ed early because of Though sample sizes were small and partici- recently because his viral load in the blood and in a head-to-head increase in ALT the clear superiority pants not randomly assigned, this study also semen is particularly high. comparison on and a 1.5-fold of efavirenz. Vicrivi- supports nPEP use. treatment-naive pa- roc is no longer be- Special Populations tients, and is now increase in ing developed as a Recommendations Clinicians should consult CDC guidelines be- being developed bilirubin. first-line therapy; its A 28-day course of a three-drug regimen of fore nPEP treatment in pregnant women. only for salvage use will be only for highly active antiretroviral therapy (HAART) Efavirenz should not be used during pregnan- therapy. And a patient taking Pfiz- salvage in patients who have failed is recommended for persons with nonoccupa- cy or among women of childbearing age at risk er’s maraviroc developed liver fail- earlier regimens. tional exposure to potentially infected body flu- for becoming pregnant because of potential ure and required a transplant, al- The case of liver failure in a pa- ids of a source known to be HIV infected when teratogenicity. The combination of d4T with though there are indications that tient taking maraviroc originally the exposure represents substantial risk for ddI has also been associated with lactic acido- other drugs the patient was taking caused concern that studies on this HIV transmission. Treatment initiation should sis causing fetal mortality. might have been to blame. medication would have to be ter- begin within 72 hours of exposure. For appropriate nPEP regimens in children, Entry inhibitors don’t attack the minated as well. This was despite If a source’s HIV status is unknown, a deci- refer to the American Academy of Pediatrics HIV virus directly, explained Dr. the fact that the drug has been used sion on whether to begin prophylaxis should be or CDC guidelines. Deeks of UCSF. Instead they block in hundreds of treatment-naive and made on a case-by-case basis. nPEP is not rec- a coreceptor on the surface of T salvage patients with no ill effects. ommended for negligible exposure risks or for The Bottom Line cells that the virus requires for en- But the patient, a 24-year-old treatment after more than 72 hours of exposure. A 28-day course of HAART is recommended try. Two such coreceptors are woman, had also been receiving nPEP should be used only for infrequent ex- for persons seeking care within 72 hours from known, CCR5 and CXCR4, which isoniazid and cotrimoxazole for posures. Persons engaging in behaviors that re- nonoccupational exposure to potentially in- are popularly called R5 and X4, re- HIV-associated infections. Her ALT sult in frequent, repeated exposure should not fectious body fluids of a known HIV-infected spectively. All three investigational levels increased more than fivefold take nPEP and instead should be provided source when the exposure represents a sub- drugs target the R5 receptor. during the 7-week screening period, with intensive risk-reduction interventions. stantial risk for transmission. Some people are known to lack and her AST increased as well. Although studies demonstrate that nPEP is the R5 coreceptor because of On the fifth day of taking mar- less likely to prevent HIV transmission when spontaneous genetic mutations. aviroc plus Combivir the patient initiated more than 72 hours after exposure, it They seem to harbor no ill effects developed rash and fever, and mar- cannot be concluded that nPEP is completely from this, leading to speculation aviroc was discontinued. The next ineffective when initiated after 72 hours from that agents that block that receptor day her liver enzymes were signif- exposure; therefore, clinicians might consider are unlikely to have serious side ef- icantly elevated (32 times normal). prescribing nPEP after exposures that present fects. No humans are known to For some reason, despite the a serious risk for transmission. lack the X4 coreceptor, on the oth- known potential for additional liv- er hand, and deleting it in mice is er toxicity, she was given a high Treatment lethal. For that reason, there has dose of acetaminophen (11 g IV) at Based on experience with individual agents in been a reluctance to develop drugs this time. Her liver enzymes con- the treatment of HIV-infected persons, pre- DR. SKOLNIK is an associate director of the that bind to the X4 receptor. tinued to worsen, and on day 16 ferred regimens include efavirenz plus lamivu- Family Medicine Residency Program at Abington R5 viruses are associated with she received a liver transplant. dine or emtricitabine with zidovudine or teno- (Pa.) Memorial Hospital, and is a coauthor of slow disease progression and are Dr. Deeks disclosed relation- fovir (a nonnucleoside-based regimen). the “Redi-Reference Clinical Guidelines” common in early HIV disease. X4 ships with several pharmaceutical Another treatment option is lopinavir and ri- handbook for handheld computers. DR. LIU is a viruses are associated with rapid companies, including being a re- tonavir plus zidovudine, with either lamivudine graduate of Jefferson Medical College, disease progression and emerge in cipient of research support from or emtricitabine (a protease inhibitor–based Philadelphia, and is a family medicine resident late disease. One worry in using R5 GlaxoSmithKline and working as a regimen).
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