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Antiretroviral-associated Hepatotoxicity Kendra D. Kress, PharmD Address Roche Laboratories Inc., 340 Kingsland Street, Nutley, NJ 07110, USA. E-mail: [email protected] Current Infectious Disease Reports 2005, 7:103-107 Current Science Inc. ISSN 15233847 Copyright © 2005 by Current Science Inc. The use of highly active antiretroviral therapy has dramatically reduced HIVassociated morbidity and mortality. As a result, patients are often being treated longer and with more complex medical regimens than ever before, increasing the risk for drug interactions and toxicities. In particular, hepatotoxicity caused by antiretroviral use has become an increasingly appreciated potential complication of drug treatment. All classes of antiretrovirals have been reported to induce liver enzyme abnormalities. However, certain antiretrovirals appear much more likely to be associated with druginduced hepatotoxicity. The risk of antiretroviral-related hepatotoxicity may be associated with patient-specific risk factors, including pre-existing viral hepatitis, baseline elevated liver function test results, female gender, and substance abuse. In addition, complex drug-drug interactions may potentate the risk of antiretroviralassociated hepatotoxicity. Coinfection with hepatitis B or hepatitis C appears to increase the risk of antiretroviral-related hepatotoxicity. Introduction The introduction of highly active antiretroviral therapy (HAART) has significantly increased the lifespan and improved the quality of life of most HIV-infected individuals [1]. However, hepatic complications associated with HIV have emerged as increasingly important adverse events for physicians who manage patients infected with HIV. Druginduced hepatotoxicity is a frequent cause of significant liver enzyme elevations in patients receiving HAART therapy. Hepatotoxicity is often and most generally de.ned as an increase in serum transaminase levels three to five times the upper limit of normal. Also commonly used to report hepatotoxicity are the National Institutes of Health/National Institute of Allergy and Infectious Diseases definitions of hepatotoxicity, which are based on a scale of severity ranging from 1 to 4 (Table 1). Most cases of antiretroviral-associated hepatotoxicity are asymptomatic and resolve spontaneously or upon discontinuation of the drug. However, antiretrovirals have also been reported to induce severe, even life-threatening cases of hepatotoxicity [2]. Although all classes of antiretrovirals have been associated with increases in serum transaminases, the non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) appear most commonly associated with inducing liver enzyme elevations. Nucleoside reverse transcriptase inhibitors (NRTIs) have been associated with a rare, but potentially life-threatening syndrome that is characterized by lactic acidosis and hepatic steatosis [3]. Background Liver disease has become one of the overall leading causes of morbidity and mortality in HIV-infected patients [4]. The precise etiology of hepatic dysfunction observed in these patients is often not clearly defined, likely because of the complex sets of molecular mechanisms involved in the pathogenesis of HIV infection and treatment. Liver dysfunction in HIV may be idiosyncratic in nature or may re.ect the effects of chronic viral hepatitis, alcohol-related liver disease, illicit drug use, or medication- induced liver toxicity. Although less common since the advent of HAART, opportunistic infections such as cytomegalovirus, mycobacteria, parasitic infection, or lymphoma are additional causes of liver disease in the HIV-infected individual. Hepatitis B (HBV) or hepatitis C (HCV) infection each cause signi.cant hepatic injury alone and may additionally increase the risk of antiretroviral-related hepatotoxicity [5]. Hepatotoxicity in HIV-infected patients is most often multifactorial as related to complex drug-drug and drug-disease state interactions. The pathophysiologic mechanisms underlying most forms of antiretroviralrelated hepatotoxicity are not fully understood. Postulated hepatotoxic mechanisms include alterations in drug metabolism, underlying liver disease, immune-mediated hypersensitivity, immune reconstitution, mitochondrial toxicity associated with lactic acidosis or lipodystrophy syndrome, and steatohepatitis [6]. Because the diagnosis and management of antiretroviral-related hepatotoxicity may be complex, some experts have proposed algorithms or checklists to be used for the diagnosis and management of hepatotoxicity in the HIV-infected patient [7] (Table 2). Table 1. NIH-NIAID grading of liver toxicity Alt Alk Phos Bilirubin Grade 1 1.25-2.5 X ULN 1.25-2.5 X ULN 1-1.5 X ULN Grade 2 > 2.5 X ULN > 2.5 X ULN > 1.5-2.5 X ULN Grade 3 > 5-10 X ULN > 5-10 X ULN > 2.5-5 X ULN Grade 4 > 10 X ULN > 10 X ULN > 5 X ULN Alk Phos-alkaline phosphate; ALT-alanine aminotransferase; NIAID-National Institute of Allergy and Infectious Diseases; NIH-National Institutes of Health; ULN-upper limit of normal. Table 2. Did this drug cause hepatitis? 1. Has this reaction been observed before? 2. Was the timing appropriate for toxicity? 3. Did toxicity improve when the drug was stopped? 4. Did toxicity reoccur when the drug was restarted? 5. Were other causes of increased ALT ruled out? ALT-alanine aminotransferase. Epidemiology The actual incidence of antiretroviral-associated hepatotoxicity is difficult to assess, and the reported values vary widely in most clinical trials and cohort studies. Controlled clinical trials have offered some data concerning antiretroviral-induced hepatotoxicity in certain patient populations; however, these studies are limited by patient inclusion/exclusion criteria, short durationof follow-up, and generally small numbers of patients [8]. More information on the incidence of antiretroviral-induced hepatotoxicity in larger and more diverse patient populations has emerged from several cohort studies and database analysis of patients treated with HAART over the past several years [9o]. Overall, severe antiretroviral-associated hepatotoxicity, defined as liver enzyme increases more than .ve times the upper limit of normal, has been reported to occur in 4.5% to 10% of HIV-infected study populations [9o,10o]. However, differences in study populations and de.nitions used for hepatotoxicity make comparisons across studies dif.cult. Hepatotoxicity Associated with Nonnucleoside Reverse Transcriptase Inhibitors The NNRTI class of antiretrovirals includes nevirapine, efavirenz, and delavirdine. Most studies reporting NNRTIrelated hepatotoxicity have found an increased incidence of hepatotoxicity with nevirapine compared with the other most commonly used NNRTI, efavirenz. Most cases of nevirapine-associated hepatotoxicity have been reported to occur within the first 6 to 12 weeks of therapy. Nevirapineinduced hepatotoxicity may often present as part of a systemic hypersensitivity-type reaction characterized by rash, fever, and eosinophilia [10o,11,12]. However, other patients develop a more nonspecific fluu-like or gastrointestinal syndrome occurring with or without elevations in liver enzymes. In some individuals, nevirapine-associated toxicity may progress rapidly to hepatomegaly with jaundice. In the most severe cases, hepatic failure develops several days later. A 2-week lead-in dosing schedule of 200 mg once daily for nevirapine is recommended by the manufacturer to reduce the incidence of the hypersensitivity reaction and hepatotoxicity. Boehringer Ingelheim (Ridgefield, CT), the manufacturer of nevirapine, conducted an extensive review of patients on nevirapine-based antiretroviral regimens, using database information from their own studies and database sets derived from other sources. In this review, most cases of nevirapine-related hepatotoxicity occurred within the first 6 weeks of therapy and were often accompanied by fever, rash, and eosinophilia [13]. No difference in hepatotoxicity was found between nevirapine and placebo after the first 6 weeks of therapy. The authors identified several independent risk factors for the development of hepatotoxicity while on nevirapine, including female gender with a CD4 count more than 250 cells per mm3, pregnancy, and male gender with a CD4 count more than 400 cells per mm3 [13]. Boehringer Ingelheim issued a letter informing health care providers of these .findings [14]. Although originally considered for this use, nevirapine is not currently recommended for HIV postexposure prophylaxis because of increased risk of hepatotoxicity and rash observed in HIV-negative persons. Patel et al. [15] con.rmed earlier reports that HIVnegative persons appear to be at higher risk for nevirapine-related adverse effects. The authors further suggested that autoimmunity may be at the root of severe toxicities associated with nevirapine because severe reactions have been found in other studies to occur most often in HIV-infected persons with high CD4 counts. Nevirapine has been widely used in pregnancy to prevent mother-to-child transmission of HIV. However, results from the PACTG1022 study demonstrated that nevirapine is associated with an increase in liver toxicity in HIV-positive pregnant women with a CD4 count more than 250 cells per mm3 or [16]. Five of 17 women stopped treatment during this study because of nevirapine-associated hepatotoxicity. Among these women, one developed Stevens-Johnson syndrome, three had increased liver enzymes (two with symptoms suggestive of hepatitis), and one experienced fulminate liver failure and died. These studies have supported the .ndings and recommendations by Boehringer Ingelheim, concluding that nevirapine should not be used in HIVinfected women with a CD4 count more than 250 cells per mm3 or in HIV-infected men with a CD4 count more than 400 cells per mm3. Several groups have tried to identify a relationship between nevirapine-induced hepatotoxicity and plasma levels of the drug, but the published results have been con.icting. Gonzalez et al. [17] reported a relationship between increased nevirapine trough levels and transaminase elevations after 12 weeks of therapy. In addition, Geel et al. [18] found that fluconazole, when coadministered with nevirapine, results in increased plasma levels of nevirapine and a subsequent increased risk for developing hepatotoxicity. In contrast, other investigators found no signi.cant correlation between plasma concentrations of nevirapine and the risk for hepatotoxicity in HIV-infected patients [19,20]. To better understand this possible correlation, work is underway analyzing potential genetic markers that could accurately predict the risk of nevirapineinduced adverse reactions. Mallal et al. [21] have reported that human leukocyte antigen type DRB1*0101 appears to be associated with development of nevirapine hypersensitivity. Clearly, more studies are needed to evaluate the relationship of nevirapine plasma levels and pharmacogenomics in the development of drug-related hepatotoxicity in de.ned populations. Other areas needing clari.cation include mechanisms of NNRTI-induced hepatotoxicity and the in.uence of immune status, gender, age, and coinfection with hepatitis B or C on the risk of adverse drug effects. Hepatotoxicity Associated with Protease Inhibitors Drug-related hepatotoxicity associated with PI use has been observed in 1% to 9.5% of treated patients in randomized clinical trials that were conducted before US Food and Drug Administration approval [22o]. In these studies, most cases of liver dysfunction were asymptomatic and resolved upon discontinuation of the PI. However, severe hepatotoxicity associated with PI use has been occasionally reported. Cohort studies have provided more information regarding the incidence of PIrelated hepatotoxicity in larger and more diverse patient populations, compared with controlled clinical trials, which have generally included only healthy patients without signi.cant comorbidities. In several retrospective and prospective cohort studies, the overall incidence of hepatotoxicity with PI use was 5% to 23%, although the de.nition of hepatotoxicity varied widely among the studies [23]. Potential risk factors for development of PIassociated hepatotoxicity have been identi.ed in several of these cohort studies. Such risk factors include infection with HBV or HCV, increased baseline alanine aminotransferase, high-dose ritonavir use, increased CD4 count, d4T use, alcohol abuse, increased age, nevirapine use, female gender, and stopping lamivudine. The only PI routinely identified as an independent risk factor for developing hepatotoxicity was high-dose ritonavir (defined as > 400 mg of ritonavir daily). There was no evidence that lowdose ritonavir use (100-200 mg/day) to boost the levels of other PIs was a risk factor for hepatotoxicity. The hepatotoxic risk of ritonavir-"boosted" PI-based regimens has not been well evaluated outside of clinical trials. However, Sulkowski et al. [24] recently evaluated PIbased antiretroviral regimens with or without ritonavir in an urban HIV clinic with a high incidence of HBV and HCV infection. Severe hepatotoxicity was observed in 12.7% (148/1161) of patients prescribed a PI-containing HAART regimen. Risk factors for developing hepatotoxicity in this study were identi.ed as detectable HCV antibody, baseline CD4 count more than 50 cells per mm3, baseline HIV RNA more than 10,000 copies per mL, baseline aspartate aminotransferase more than 35 U per L, and use of indinavir or saquinavir/ritonavir (800 mg ritonavir/day). Race, gender, age, HBV status, concurrent NNRTI use, change in CD4 count, or viral load during treatment were not identified as risk factors for hepatotoxicity. No difference in the incidence of hepatotoxicity was found between lopinavir/ritonavir-based regimens and nel.navirbased regimens in patients with or without HCV infection. However, the researchers did find a 2.5-fold increased risk of hepatotoxicity overall, among patients with HCV infection. In this study, the authors were unable to determine the rate of hepatotoxicity with PI-based regimens including atazanavir, amprenavir, fosamprenavir, or saquinavir/ritonavir (1000 mg/100 mg twice daily). Clearly, more studies are needed to evaluate PI-associated hepatotoxicity, especially with newer PI-based antiretrovirals including atazanavir, fosamprenavir, and saquinavir plus low-dose ritonavir. Hepatotoxicity Associated with Nucleoside Reverse Transcriptase Inhibitors The use of two drugs from the NRTI class of antiretrovirals is considered to be the backbone of most HAART regimens. This class has been associated with a rare but serious syndrome characterized by lactic acidosis and hepatic steatosis [25]. Lactic acidosis syndrome and other adverse effects of NRTIs are thought to be mediated by inhibition of human DNA polymerase ð¨, resulting in mitochondrial dysfunction [26]. Symptoms of NRTI-related lactic acidosis may include fatigue, exercise intolerance, dif.culty breathing, nausea, vomiting, abdominal pain, and weight loss. Diagnosis is con.rmed by a serum lactate level more than 3 mmol per L. Upon diagnosis, all antiretrovirals should be stopped. Treatment for lactic acidosis remains mostly supportive; however, studies are currently being conducted on the prevention and treatment of lactic acidosis, with essential cofactors including thiamin and riboflavin. The risk factors for developing lactic acidosis in HIV infected patients receiving HAART are currently unknown. Certain NRTIs, such as d4T and ddI, appear to be more likely to cause mitochondrial toxicity; however, data on the incidence of lactic acidosis with specific NRTIs and in combination with other antiretrovirals are limited. It is unknown if HCV infection is a risk factor for development of lactic acidosis in patients on NRTIs. In patients treated for HCV infection, concomitant use of ribavirin and didanosine or stavudine increases the risk of lactic acidosis and is not recommended [27]. HIV/Hepatitis C Virus Coinfection In the United States, up to 30% of HIV-infected persons are coinfected with HCV. Preliminary data suggested that coinfected patients are more likely to develop HAARTrelated hepatotoxicity than are HIV-infected individuals. However, attributing incidences of hepatotoxicity to antiretroviral use is dif.cult because of the presence of HCV-mediated liver damage, frequent comorbid risk factors (eg, alcohol ingestion and illicit drug use). In addition, the phenomenon of immune reconstitution occurring after the initiation of HAART may also indirectly contribute to elevation of serum transaminase levels commonly observed in coinfected treatment [27]. HIV infection appears to have a deleterious effect on progression of HCV, infection resulting in higher rates of .brosis and cirrhosis in patients with coinfection, although this effect remains to be completely characterized [28]. Additional preliminary data indicate that the transaminase levels decrease or even normalize in coinfected women undergoing HAART, possibly because of the later, more bene.cial, effects of immune reconstitution on hepatic function in this population [29]. Conversely, Uberti-Foppa et al. [30] recently showed that 6 months of HCV treatment before initiation of HAART reduced the risk of antiretroviral-related toxicity in patients able to defer HAART based on their immune status. In a study published in early 2004, nevirapine-containing HAART regimens were associated with faster progression of liver fibrosis in coinfected patients, compared with PI-based HAART [31]. More evidence linking nevirapine and hepatotoxicity in HIV/HCV-coinfected patients was presented at the Seventh International Congress on Drug Therapy in HIV Infection in November, 2004. Aranzabal et al. [32] reported that among coinfected patients receiving HAART, the risk of a fivefold increase in liver transaminases was greater in patients with grade 3 to 4 liver fibrosis, compared with those with grade 1 to 2 liver fibrosis. Nevirapinecontaining regimens had a higher incidence of transaminitis than efavirenz or non- NNRTI-based regimens. Many factors must be carefully considered when initiating treatment of HIV in coinfected patients. In addition to such standard parameters as CD4 count and HIV viral load, liver function tests, HCV viral load and genotype, hepatic imaging, and, in most patients, a liver biopsy should also be obtained [33]. Antiretrovirals shown be associated with an increased risk of hepatotoxicity coinfected patients, such as nevirapine, should be used with extreme caution, or not at all, in most coinfected patients. It is important to weigh the risks and benefits HAART therapy in patients with hepatitis. Unfortunately, research is lacking concerning the relative risk of hepatotoxicity with speci.c drugs and antiretroviral regimens this patient population [34o]. Many studies are underway to address the optimal timing and modulation of HCV therapy in coinfected patients. Conclusions Antiretroviral-associated hepatotoxicity is an important consideration in the management of HIV-infected patients, especially those with comorbidities that may add additional risk for liver injury. All classes of antiretrovirals have been associated with liver enzyme abnormalities; however, the incidence of speci.c antiretroviral-related hepatotoxicity has not been well de.ned in clinical studies. Nevirapine and high-dose ritonavir are the only antiretrovirals found to be a signi.cant risk factor development of drug-related hepatotoxicity. Although con.icting data exist, HBV and HCV coinfection appear to be signi.cant risk factors for hepatotoxicity in patients receiving HAART. References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: o Of importance oo Of major importance 1. Palella FJ Jr, Delaney KM, Moorman AC, et al.: Declining morbidity and mortality among patients with advanced human immunode.ciency virus infection. HIV Outpatient Study Investigators. N Engl J Med 1998, 338:853-860. 2. Puoti M, Torti C, Ripamonti D, et al.: HIV-HCV Co-Infection Study Group. Severe hepatotoxicity during combination antiretroviral treatment: incidence, liver histology, and outcome. J Acquir Immune De.c Syndr 2003, 32:259-267. 3. Ogedegbe AO, Sulkowski MS: Antiretroviral-associated liver injury. Clin Liver Dis 2003, 7:475-499. 4. Bica I, McGovern B, Dhar R, et al.: Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clin Infect Dis 2001, 32:492-497. 5. Dieterich D: Managing antiretroviral-associated liver disease. J Acquir Immune De.c Syndr 2003, 34(Suppl 1):S34-S39. 6. Pol S, Lebray P, Vallet-Pichard A: HIV infection and hepatic enzyme abnormalities: intricacies of the pathogenic mechanisms. Clin Infect Dis 2004, 38(Suppl 2):S65-S72. 7. Nierenberg DW: "Did this drug cause my patient s hepatitis?" and related questions. Ann Intern Med 2002, 136:480-483. 8. Sabin CA: Pitfalls of assessing hepatotoxicity in trials and observational cohorts. Clin Infect Dis 2004, 38(Suppl 2):S56-S64. 9.o Becker S: Liver toxicity in epidemiological cohorts. Clin Infect Dis 2004, 38(Suppl 2):S49-S55. This is a nice review of important cohort studies that have reported risk factors associated with increased risk of hepatotoxicity. 10.o Dieterich DT, Robinson PA, Love J, et al.: Drug-induced liver injury associated with the use of nonnucleoside reverse-transcriptase inhibitors. Clin Infect Dis 2004, 38(Suppl 2):S80-S89. This is an excellent discussion of NNRTI-associated hepatotoxicity and supporting evidence. 11. Kontorinis N, Dieterich DT: Toxicity of non-nucleoside analogue reverse transcriptase inhibitors. Semin Liver Dis 2003, 23:173-182. 12. Manfredi R, Calza L, Chiodo F: Efavirenz versus nevirapine in current clinical practice: a prospective, openlabel observational study. J Acquir Immune De.c Syndr 2004, 35:492-502. 13. Stern JO, Robinson PA, Love J, et al.: Nevirapine hepatic safety project. Paper presented at the XIV International AIDS Conference. Barcelona, Spain, July 7-12, 2002. 14. Shepard K: Clari.cation of risk factors for severe, life threatening and fatal hepatotoxicity with Viramune (nevirapine) [letter]. Rigde.eld, CT: Boehringer Ingelheim Pharmaceuticals; 2004. 15. Patel SM, Johnson S, Belknap SM: Serious adverse cutaneous and hepatic toxicities associated with nevirapine use by non-HIV-infected individuals. J Aquir Immune De.c Syndr 2004, 35:120-125. 16. For the PACTG 1022 Study Team: Maternal toxicity with continuous nevirapine in pregnancy: results from PACTG1022. J Acquir Immune De.c Syndr 2004, 36:772-776. 17. Gonzalez D, Jiménez-Nácher I, Romero M, et al.: Changes in nevirapine plasma concentrations along 48 weeks and relationship with transaminase elevations [abstract 856]. Antivir Ther 2003, (Suppl 1):S425. 18. Geel J, Pitt J, Orrell CJ, et al.: The effect of fluconazole on nevirapine pharmacokinetics [abstract WeOr1239]. Program and abstracts of the XV International AIDS Conference. Bangkok, Thailand, July 11-16, 2004. 19. Almond LM, Bof.to M, Hoggard PG, et al.: The relationship between nevirapine plasma concentrations and abnormal liver function tests. AIDS Res Hum Retroviruses 2004, 20:716-722. 20. Dailly E, Billaud E, Reliquet V, et al.: No relationship between high nevirapine plasma concentration and hepatotoxicity in HIV-1-infected patients naive of antiretroviral treatment or switched from protease inhibitors. Eur J Clin Pharmacol 2004, 60:343-348. 21. Mallal S, Martin A, Cameron P, et al.: Predisposition to nevirapine hypersensitivity associated with HLA-DRB1 *0101 abrogated by low CD4+ T cell counts. Program and abstracts of the XV International AIDS Conference. Bangkok, Thailand, July 11-16, 2004. 22.o Sulkowski MS: Drug-induced liver injury associated with antiretroviral therapy that includes HIV-1 protease inhibitors. Clin Infect Dis 2004, 38(Suppl 2):S90-S97. This is a recent and comprehensive review of PI-related hepatotoxicity. 23. Sulkowski MS: Hepatotoxicity associated with antiretroviral therapy containing HIV-1 protease inhibitors. Semin Liver Dis 2003, 23:183-194. 24. Sulkowski MS, Mehta SH, Chaisson RE, et al.: Hepatotoxicity associated with protease inhibitor-based antiretroviral regimens with or without concurrent ritonavir. AIDS 2004, 18:2277-2284. 25. Montessori V, Harris M, Montaner JS: Hepatotoxicity of nucleoside reverse transcriptase inhibitors. Semin Liver Dis 2003, 23:167-172. 26. Montaner JS, Cote HC, Harris M, et al.: Nucleoside-related mitochondrial toxicity among HIV-infected patients receiving antiretroviral therapy: insights from the evaluation of venous lactic acid and peripheral blood mitochondrial DNA. Clin Infect Dis 2004, 38(Suppl 2):S73-S79. 27. Braitstein P, Palepu A, Dieterich D, et al.: Special considerations in the initiation and management of antiretroviral therapy in individuals coinfected with HIV and hepatitis C. AIDS 2004, 18:2221-2234. 28. Bonacini M: Liver injury during highly active antiretroviral therapy: the effect of hepatitis C co-infection. Clin Infect Dis 2004, 38(Suppl 2):S104-S108. 29. French AL, Benning L, Anastos K, et al.: Longitudinal effect of antiretroviral therapy on markers of hepatic toxicity: impact of hepatitis coinfection. Clin Infect Dis 2004, 39:402-410. 30. Uberti-Foppa C, De Bona A, Morsica G, et al.: Pretreatment of chronic active hepatitis C in patients coinfected with HIV and hepatitis C virus reduces the hepatotoxicity associated with subsequent antiretroviral therapy. J Acquir Immune De.c Syndr 2003, 33:146-152. 31. Macias J, Castellano V, Merchante N, et al.: Effect of antiretroviral drugs on liver .brosis in HIV-infected patients with chronic hepatitis C: harmful impact of nevirapine. AIDS 2004, 18:767-774. 32. Aranzabal L, Casado JL, Moya J, et al.: HAART-associated hepatotoxicity in HIV/HCV co-infected patients: the role of liver histologic damage and drug levels [abstract PL14.1]. Program and abstracts from the 7th International Congress on Drug Therapy in HIV Infection. Glasgow, Scotland, November 14-18, 2004. 33. Soriano V, Massimo P, Sulkowski, et al.: Care of patients with hepatitis C and HIV co-infection. AIDS 2004, 18:1-12. 34.o Powderly WG: Antiretroviral therapy in patients with hepatitis and HIV: weighing risks and benefits. Clin Infect Dis 2004, 38(Suppl 2):S109-S113. This is a very useful discussion that brings to light important therapeutic considerations when treating HIV in coinfected patients.