Mortality related to human immunodeficiency virus-1 (HIV-1) infection has declined dramatically since 1996 in Europe and the United States with the widespread use of high activity antiretroviral therapy (HAART). Conversely, end-stage liver disease (ESLD), mainly caused by hepatitis C virus (HCV), is becoming an important cause of death among HIV-1-infected patients . A Spanish single-center study  analyzed the cause of 235 deaths in 4471 patients on HAART (5%) from 1997 to 2004. The number of patients who died from ESLD increased from 8% in 1997 to 41% in 2004, and in recent years this condition has become the leading cause of death in HIV-infected patients. In comparison with the general population of a similar age, deaths due to liver disease were 11 times higher in HIV-infected patients. Orthotopic liver transplantation (OLT) is the only therapeutic option for patients with ESLD [3-6]. However, until a few years ago, infection by HIV was an absolute contraindication to any transplant. The poor prognosis and fear that transplant-associated immunosuppression would speed up the progression to AIDS or increase the risk of opportunistic infections ruled out OLT . The spectacular improvement in prognosis observed in HIV-infected patients after the introduction of HAART in 1996 has meant that transplant is now being reconsidered in patients with ESLD. This paper does not aim to provide an exhaustive review of the matter at hand, which has already been amply studied in other recent reviews [8-13]. Our main objective is to define the criteria to select HIV-infected patients for OLT, taking into account that this field is evolving continuously and the indications for OLT or management of these patients may change as more evidence becomes available.
EXPERIENCE OF OLT IN HIV-INFECTED PATIENTS IN THE HAART PERIOD (1996-2006)
Initial attempts at OLT in HIV-infected patients before the introduction of HAART regimens (before 1996) produced very poor results. Consolidating the most important case series published [14-17], the three-year survival was only 44%. Most patients died because of HIV-disease progression, the graft function being normal in many cases. However, since the introduction of HAART, HIV-infected recipients of liver transplantation have had improved short- and mid-term survival. In North America and Europe in the last 5 years, more than 200 OLTs were performed [9,10,18-33] (Table 1). Survival was greater than 70% in most series with different periods of follow-up. In more than two-thirds of cases, the primary indication for OLT was HCV coinfection. Although cases came from different institutions, the criteria used for liver transplantation were quite similar. In general, candidates did not have prior history of opportunistic infections, CD4+ counts were >100 cells/μL, and plasma HIV-RNA was undetectable on HAART (or drugs were available for successful treatment in the post-OLT period) [6,7]. In a multicenter and multinational retrospective study performed by Ragni et al  that included 23 HIV-infected patients who underwent OLT, survival at three years was 73% and 79% (p = not significant) for HIV-infected and non-HIV-infected recipients, respectively (Table 2). Similar rates were seen for graft survival. In all cases published in the HAART era, the main cause of death was due to hepatitis C recurrence. In any case, 3-year survival in HIV-infected recipients in the HAART period was almost 30% higher than in the pre- HAART era [14-17] and, therefore, at present, HIV infection is no longer a formal contraindication to transplant. However, de Vera et al  recently published a single-center series of HIV/HCV-coinfected patients with the longest mean followup (27±5 months). They undertook a case–control study comparing the progression of 27 HIV/HCV-coinfected patients with 54 HCV-monoinfected patients (control group) who underwent OLT (Table 2). Five-year survival was poorer in the coinfected patients (33% versus 72%), although this difference was not statistically significant (p = .07) .
| ||TABLE 1. Liver transplantation in HIV-infected patients: main series of cases (≥ 5) in the late HAART era (2002-2007) |
|TABLE 2. Three-year survival of patients with and without HIV-infection who underwent liver transplantation before and during the HAART period |
In Spain, the OLT program in HIV-infected patients began in January 2002 (GESIDA unpublished data). To date, 117 liver transplantations have been performed. More than 96% of patients were HIV/HCV-coinfected. There were 31 deaths (26.5%) after a median follow-up of 21 months.
MAGNITUDE OF ESLD IN EUROPE AND NORTH AMERICA
According to current estimates, there are around 540,000 HIV-infected patients in Western European countries . Prevalence of HCV coinfection in European HIV-infected patients is 33% . Therefore, the estimated number of HIV/HCV-coinfected patients is around 180,000. In a cross-sectional study performed in Spain , 8% of coinfected patients had clinical or histological criteria of cirrhosis and 17% met the Spanish criteria to be put on an OLT waiting list. Therefore, the potential number of candidates for OLT in Europe would be around 3100.
CRITERIA FOR LIVER TRANSPLANT OF HIV-INFECTED PATIENTS
Liver disease criteria
Criteria concerning liver disease are the same as for the non-HIV-infected population, with the main indication for OLT in HIV-infected patients being ESLD caused by HCV coinfection. Less frequent indications were hepatitis B virus (HBV) coinfection (either acute or ESLD) and liver cancer. The British HIV Association, in conjunction with the UK and Ireland Liver Transplantation Centre, has recently published a Consensus Guideline reviewing both liver disease criteria and HIV-infection criteria . In this guide, indications for liver transplantation include acute liver failure, decompensated liver disease [with ascites, encephalopathy (it is important to exclude HIV-related dementia), variceal bleeding that is difficult to manage with standard therapies, poor liver function (e.g., albumin <30 g/L, international normalized ratio (INR) >1.5, and elevated serum bilirubin >45 μ/L)], and hepatocellular carcinoma detected during regular tumor surveillance. Criteria for liver transplantation in patients with hepatocellular carcinoma are: no more than three tumor nodules, no nodule >5 cm in diameter, absence of macroscopic portal vein invasion, and absence of recognizable extrahepatic disease . Preliminary Italian experience showed good results in five cases . After a median follow-up of seven months, four cases remained alive with no recurrence of hepatocellular carcinoma. One patient died as a result of cardiac infarction with normal graft function and no evidence of recurrence.
HIV-infection criteria in Spain
In Spain, a multidisciplinary task force  has recently defined clinical, immunological, and virological criteria, which are described in the following paragraphs.
Ideally, patients should not have suffered previously from AIDS-defining diseases, as these may have a greater risk of reactivation. However, the improved prognosis post-HAART means that some authors are in favor of withdrawing exclusion criteria for some opportunistic infections which can be efficaciously treated and prevented, such as tuberculosis, candidiasis, and Pneumocystis jirovecii pneumonia [9,11,23]. The Spanish task force considered that the experience with other opportunistic infections and tumors (like Kaposi sarcoma) in a setting of HIV is still too limited to make any recommendations.
All groups have agreed that the CD4+ lymphocyte count should be >100 cells/μL for OLT [9-11,22]. This figure is lower than that used for kidney transplantation (e.g., CD4 >200 cells/μL) because patients with cirrhosis often have lymphopenia due to hypersplenism, which leads to a lower absolute CD4+ count, despite high CD4+ percentages and good virological control of HIV.
The essential criteria for OLT is that the patient must be able to have effective and long-lasting antiretroviral therapy during the post-transplant period [9-11,39]. The ideal situation is one in which the patient tolerates HAART before transplant and is ready for the transplant with undetectable plasma HIV viral load by ultra-sensitive techniques (<50 copies/mL). Nevertheless, this is not always possible for several reasons: 1) In some patients with ESLD, it may be difficult to maintain an undetectable HIV viral load in plasma because they often experience intolerance or toxicity related to antiretroviral drugs, which must then be stopped. In these cases, and to avoid resistance, it is better to save antiretroviral therapy for the post-transplant period; 2) some patients remain viremic with HAART. In these cases, it is mandatory to carry out antiretroviral sensitivity testing (genotypic or phenotypic resistance testing)  to ascertain the real therapeutic options. The evaluating team and HIV experts will evaluate whether the patient has effective and durable rescue therapy; and 3) some patients do not have an indication for HAART as they are long-term non-progressors (LTNP) or do not have immunological criteria (CD4+ lymphocyte count above 350 cells/μL) or clinical criteria to begin HAART and, therefore, they have viremia that is detectable in plasma. In this setting, it is unknown whether and when (pre-transplant or post-transplant) it would be beneficial to initiate HAART to reach an undetectable HIV viral load in plasma.
Furthermore, to include an HIV-infected patient on the OLT waiting list, the candidate must have a favorable psychiatric evaluation. Patients who actively consume drugs will be excluded. In Spain, the recommended consumption-free periods are two years for heroin and cocaine  and six months without addiction for other drugs (e.g., alcohol). Patients who are on stable methadone maintenance programs are not excluded from transplant and can continue on such programs after the transplant . Finally, as is the case with any transplant candidate, HIV-infected patients must show an appropriate degree of social stability to ensure adequate care in the post-transplant period.
HIV criteria in other European and North America countries
Most liver transplant groups in Europe and North America are using similar HIV criteria, that are summarized in Table 3 [27,37,39,42]. We would like to point out that, currently, to have a previous opportunistic infection is not a strict exclusion criterion by itself. In fact, a National Institutes of Health (NIH)-sponsored study has recently updated the inclusion criteria for opportunistic complications , and only those diseases without therapy remain as exclusion criteria for liver transplantation (e.g., progressive multifocal leukoencephalopathy, chronic cryptosporidiosis, multidrug- resistant systemic fungal infections, primary central nervous system lymphoma, and visceral Kaposi’s sarcoma) . On the other hand, a CD4+ count of >200 cells/μL is the cut-off used in Italy  and the UK  unless the patient has decompensated cirrhosis or portal hypertension, respectively, in which cases they use the same CD4+ cell threshold used in Spain and the United States (100 cells/μL) [39,42].
| ||TABLE 3. HIV criteria for OLT in some European countries and the USA |
Special considerations in HIV-infected patients
OLT in HIV-infected patients is a complex scenario that requires a multidisciplinary approach [9-11,39]. Sites wishing to carry out transplants in HIV-positive patients must have a multidisciplinary team which can periodically evaluate these patients during the pre- and post-transplant periods. The team should include members from the liver transplant team (medical and surgical), infectious disease and HIV specialists, a psychologist/psychiatrist, an expert on alcoholism and drug abuse, and a social worker.
CONTROVERSIAL ISSUES IN THE PRE-TRANSPLANT PERIOD
Waiting list mortality in HIV-infected patients with ESLD is very high. This is because survival of HIV-infected patients with decompensated cirrhosis is much lower than in HIV-negative patients [44-46]. Pineda et al  have recently shown in a multicenter case–control study performed in Andalusia (Spain) that the outcome of cirrhosis after the first decompensation in HIV/HCV-coinfected patients is much worse than in the mono-HCV-infected population. Survival at one, two, and five years for coinfected and monoinfected populations was 54% versus 74%, 40% versus 61%, and 25% versus 44%, respectively. In another study , the same group of investigators identified as independent predictors of a poor outcome in HIV/HCV-coinfected patients, the severity of liver disease [Child-Turcotte-Pugh (CTP) classification or development of hepatic encephalopathy as the first hepatic decompensation] and the level of cellular immunosuppression (<100 CD4+ cells/μL). On the other hand, HAART was associated with reduced mortality .
One Spanish study followed the evolution of 104 HIV-infected patients with cirrhosis after their first hepatic decompensation or hepatocellular carcinoma . Median survival time of the cohort was 14 months, similar to that of Merchante’s cohort (13 months) . This study included HCV- and non-HCV-infected patients and found no significant differences in survival according to the etiology of cirrhosis, suggesting that HIV-infected patients have an overall poor outcome regardless of the nature of their liver disease. Furthermore, the model for end-stage liver disease (MELD) score was the only factor independently associated with mortality. This is of relevance because MELD is increasingly being used to establish the prognosis of patients with cirrhosis and, consequently, to indicate liver transplantation.
Once an HIV-infected patient with ESLD is included on the transplant waiting list, mortality often remains very high (>60%). In our center, as in most Spanish centers, this occurs mainly because prioritization for organ allocation is predominantly established on the basis of time on the waiting list. In comparison, the annual mortality rate for non-HIV-1-infected patients while on the liver transplant waiting list in our center ranged between 8% and 12% in recent years. High mortality rates of HIV/HCV-coinfected patients with ESLD waiting for liver transplantation has been previously reported in two studies [47,48]. In one of these studies , mortality rates during pre-transplant evaluation among HIV-positive (N=58) and HIV-negative (N=1359) patients were 36% and 15%, respectively (p <.001).
For these reasons, physicians attending cirrhotic HIV-infected patients should prospectively follow them, and they should be evaluated early for OLT after the first clinical decompensation of the liver disease: ascites, hepatic encephalopathy, spontaneous bacterial peritonitis, gastroesophageal variceal bleeding, and/or jaundice. Similarly, patients whose cirrhosis is associated with hepatocellular carcinoma should also be evaluated. Both, prevention and effective treatment of these complications may improve the likelihood of patient survival until OLT [49,50].
Concerning antiretroviral therapy, these patients should follow the general recommendations [51,52] and their liver function must be closely monitored for signs of hepatotoxicity. Furthermore, some antiretroviral drugs may be contraindicated in cirrhotic patients (e.g., didanosine, nevirapine, full-dose ritonavir) and their dosing should be adjusted according to the degree of hepatic impairment [52-55]. Therapeutic drug monitoring (TDM) may be useful for efavirenz and protease inhibitors. Indinavir and atazanavir can increase the levels of unconjugated bilirubin by inhibiting UDP-glucuronosyltransferase. As total bilirubin is a component of both CTP and MELD scores, their values in patients taking these drugs should be interpreted cautiously.
Organ transplantation in HIV-infected patients has raised ethical problems which have not yet been completely resolved. However, currently most groups agree that HIV-infected patients should receive the same treatment as other patients and be included on waiting lists under the same conditions .
Pre-transplant evaluation of donor and recipients should be the same as for non-HIV-infected patients. With respect to the type of donor to be used in HIV-infected patients, most solid organ transplants have been carried out using cadaveric donors. In recent years, and as a consequence of the increased demand for organs, the number of living donors has increased. Nevertheless, the benefits of this technique have yet to be demonstrated in the HIV-infected population.
ISSUES IN THE POST-TRANSPLANT PERIOD
After OLT, patients and physicians enter a new and complex clinical situation. Patients must receive a large quantity of drugs, and this can compromise adherence. In addition to HAART, which they may be accustomed to, they must take immunosuppressive drugs and sustain habitual prophylaxis against opportunistic infections and take other medications to manage complications that frequently develop after OLT (e.g., diabetes, hypertension). Patients on methadone programs must continue on these. HCV-coinfected patients may require therapy with interferon alfa and ribavirin. In this new scenario, what are the current data regarding the course of HIV infection, immune suppression and allograft rejection, pharmacological interactions among the different type of drugs used, and the course of HCV and HBV infection recurrence?
Patients usually follow the same HAART regimens that they took in the pre-OLT period, but these regimens can be changed in the post-OLT period on an individual basis to choose the easiest regimen to adhere to, with lower potential for pharmacological interactions between immunosuppressive agents and anti-HCV drugs and lower liver toxicity. In any case, the general recommendations for antiretroviral therapy in the adult should be followed [51,52] and liver function must be closely monitored in order to detect hepatotoxicity. Furthermore, HIV-infected patients should be given constant support and impressed with the importance of rigorous adherence to all their treatment schedules.
There are solid data showing that HIV-infected patients do not have an increased risk of post-operative complications or a higher incidence of opportunistic infections or tumors than HIV-negative patients [9-12]. CD4+ cell counts and plasma HIV viral load remain stable and undetectable, respectively, as long as HAART can be administered. Furthermore, immunosuppressive drugs (e.g., calcineurin inhibitors, mycophenolic acid, prednisone) can reduce HIV replication in two ways: first, by reducing the immune activation induced by HIV; and, second, because calcineurin inhibitors and mycophenolic acid have direct anti-HIV activity [10,11]. Furthermore, mycophenolic acid enhances abacavir action against HIV .
Immunosuppression and rejection
There are no specific immunosuppressive regimens for HIV-infected patients, and each center uses the same regimens as for HIV-negative patients. As mentioned previously, the use of standard immunosuppressive therapy in patients with well-controlled HIV infection did not increase their susceptibility to opportunistic infections or malignant conditions [9-12]. Therefore, HIV-infected patients should follow the same prophylaxis protocols as the general population. In some studies, the rates of allograft rejection were higher than in the HIV-negative population. The cause of this phenomenon is unknown, and it is particularly noticeable in kidney transplants [13,58,59], suggesting that HIV does not protect against allograft rejection. At present, the best regimen for immune suppression in OLT HIV-infected recipients is unknown.
There are important pharmacological interactions between antiretrovirals and immunosuppressive or anti-HCV drugs which may be clinically relevant [52-55,60-72]. Cyclosporine A, tacrolimus, and sirolimus are metabolized in the liver by cytochrome P-450, whereas mycophenolate mofetil undergoes glucuronization in the liver. Antiretrovirals can act as inhibitors or inducers of these enzymatic systems. When they act as enzyme inhibitors (e.g., protease inhibitors; PIs), they increase the concentrations of these immunosuppressants and can lead to toxicity. For this reason, doses must be markedly reduced (e.g., tacrolimus 1 mg/week in patients taking Kaletra®) [63-65]. These interactions have caused some episodes of acute rejection in patients who stopped PIs while taking calcineurin inhibitors. On the other hand, when antiretrovirals act as enzyme inducers (e.g., non-nucleoside reverse transcriptase inhibitors; NNRTIs), they reduce drug levels and can trigger rejection, and therefore doses of most immunosuppressive drugs must be increased . Accordingly, it is important to know very well the possible drug interactions and closely monitor the levels of immunosuppressive drugs. In addition, there are important overlapping acute and chronic toxicities between antiretroviral and immunosuppressive drugs that should be taken into account (e.g., liver, renal and/or bone marrow toxicities, hyperlipidemia, diabetes, osteoporosis) [11,12,51,52]. As a consequence of these important interactions between some antiretroviral families (e.g., NNRTI or PI) and immunosuppressive drugs, some researchers are using enfuvirtide (T-20) plus two nucleoside reverse transcriptase inhibitors (NRTIs) to avoid these interactions .
There also are important pharmacodynamic interactions between some NRTIs (e.g., didanosine, stavudine, and zalcitabine) and ribavirin, a drug used in combination with pegylated interferon to treat HCV infection recurrence in OLT recipients. These interactions have been reviewed in-depth elsewhere [74,75].
Finally, given the speed with which new antiretrovirals appear and thus generate unknown interactions, physicians are recommended to consult updated databases on drug interactions [54,55].
Course of HCV infection recurrence
After OLT, HCV infection recurrence is universal, regardless of whether the patient is infected by HIV or not. At present, it is not known whether recurrence is worse in the HIV-positive patient than in the HIV-negative patient . Similarly, there is insufficient experience on the efficacy and safety of therapy with interferon and ribavirin in HIV/HCV-coinfected transplant patients. Rapid progression of HCV-related liver disease in HIV-infected recipients would be a major drawback and would lead to a shortened life expectancy of these patients. In fact, currently it is the most important cause of death.
In the experience of Samuel’s group, five of seven HIV/HCV-coinfected patients survived after a median follow-up of 21 months . There was an early (<2 months) and severe relapse of HCV infection in all cases. Chronic hepatitis developed in all but one case within the first year after transplantation. Samuel and colleagues  observed mitochondrial toxicity in most patients studied. Liver steatosis was present in six of seven liver biopsies and abnormal respiratory chain (complex IV) function was detected in the five patients studied. It is important to point out that dideoxyinosine (ddI) was included in the HAART regimen in four cases. These investigators also detected a faster progression of liver fibrosis at 1 and 2 years in HIV-infected recipients in comparison with monoinfected HCV patients (1.5±1.4 versus 0.8±0.5) . Two-year survival with fibrosis less than F3 stage was 36% in HIV/HCV-coinfected and 74% in monoinfected HCV patients (p <.02) . In the multivariate analysis the only factor associated with the rate of fibrosis was HIV coinfection. In another study, de Vera et al  also found that in comparison to HCV-monoinfected patients, HIV/HCV-coinfected patients had a higher likelihood of developing cirrhosis or dying from an HCV-related complication [relative risk (RR) 2.6, 95% CI 1.06-6.35].
There are some preliminary data on the efficacy of treatment of HCV recurrence in OLT HIV-infected patients with interferon or pegylated-interferon alfa and ribavirin, which are summarized in Table 4. In these small studies [10,26,28,77-81], the mean rate of sustained virological response (SVR) by intention-to-treat analysis was 25.7%. However, although this rate of SVR in HIV/HCV-coinfected patients is very low, it is similar to the rate of SVR observed in OLT HCV-monoinfected patients in two case–control studies [28,79] (Table 4).
| ||TABLE 4. Summary of studies evaluating the effectiveness of treatment of HCV reinfection in OLT with pegylated interferon alfa plus ribavirin |
Mortality data are controversial. In some single sites, the experience is very negative. Norris et al  reported that five of seven British HCV-coinfected patients who underwent OLT died after a median follow-up of around 6 months. Most cases died of complications due to recurrent HCV infection and sepsis, despite anti-HCV therapy in three of them . In a study by Samuel and colleagues , 2-year survivals were 74% and 92% in coinfected and monoinfected patients, respectively (p = .07). In the multivariate analysis, survival was only related to MELD score . Ragni et al  also observed in a multicenter study a trend of a poorer 3-year outcome in HCV/HIV-coinfected patients in comparison with HIV-negative recipients (p = .06). de Vera et al  observed the same trend in their single-center study of HIV/HCVcoinfected patients with the longest mean follow-up (27±5 months). They did a case–control study comparing the progression of 27 HIV/HCV-coinfected patients with 54 HCV-monoinfected patients who underwent OLT (Table 2). Five-year survival was poorer in the coinfected patients (33% versus 72%), although this difference was not statistically significant (p = .07). Risk factors for poor survival were African-America race, MELD score >20, HAART intolerance post-OLT, and post-OLT plasma HCV RNA >30 million IU/mL . Conversely, other American [59,60] and European [27,33,79, GESIDA unpublished data] studies are showing better results, with low mortality rates at mid-term (3 years). In one study performed in Spain, Miró et al  analyzed the prognostic factors of mortality in 60 consecutive HCV OLT HIV-infected recipients. Advanced donor age (>65 years) (p = .08) and developing graft cirrhosis (p = .03) due to HCV recurrence were the two variables associated with death in the multivariate analysis. Prospective studies with longer duration (5-10 years) are needed to confirm or refute these findings.
All HIV-infected patients with ESLD should be considered as candidates for OLT if they meet the inclusion criteria stated here. There is increasing experience with OLT in HIV-infected patients and current data show that short- and mid-term survival is the same as that of HIV-negative patients. HIV infection can be easily controlled with antiretroviral therapy during the post-transplant period. The evaluation and the pre- and post-OLT management of this complex scenario should include an interdisciplinary team composed by members of the OLT team (hepatologists and surgeons), infectious disease and HIV specialists, psychologists, social workers, and members of alcohol and other drug detoxification programs. Interactions between immunosuppressive agents and antiretrovirals, especially protease inhibitors and, to a lesser extent, NNRTIs, are important and require close monitoring of immunosuppressor plasma levels. Patients do not have a greater risk of opportunistic infections or tumors, and therefore should follow the same prophylaxis protocols as the non-HIV-infected population. In patients receiving OLT for HCV cirrhosis, recurrence of HCV infection is universal during the post-transplant period and it is the main concern. It is unknown whether this reinfection has a worse outcome than in the HIV-negative patient, and there is insufficient experience with pegylated interferon and ribavirin in this population. However, preliminary data showed low rates of cure (around 20%).
Future research needs
There are several issues that should be explored in the future: 1) Since survival is much shorter in HIV/HCV-coinfected patients, strategies to make OLT available sooner after patient assignment to this procedure should be emphasized; 2) Currently, there are many sites with active OLT programs in HIV-infected patients, but the number of cases is too small in every single institution to obtain valuable clinical information. The NIH-sponsored multicenter OLT trial (2005-2007) that is being performed in the USA will be very useful. A FIPSE-funded study (2006-2008) is also being performed in Spain. For these reasons, it will be important to create an international registry of cases, using standardized case report forms, to establish the mid- (5 years) and long-term (10 years) survival of OLT in HIV-infected patients and compare it with the non-HIV-infected population; 3) To improve the management of pharmacokinetic and pharmacodynamic interactions between immunosuppressive, antiretroviral, and anti-HCV drugs; 4) To know the optimum immunosuppressive regimens for HIV-infected recipients; and, 5) To know the natural history of OLT HCV-reinfection and to improve the management and treatment of HCV recurrence. Prospective studies evaluating the effectiveness of pre-transplant anti-HCV therapy in HIV-infected patients or early (pre-emptive) post-OLT anti-HCV therapy are warranted.
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This document is dedicated to all our patients and has come about thanks to the collaboration of many people and institutions.
Partially supported by the Fundación para la Investigación y Prevención del Sida en España (FIPSE grants 36465/03 and TOH/VIH-05); the Agencia de Ensayos Clínicos del Grupo de Estudio de Sida (AEC-GESIDA) de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC); the Red Temática Cooperativa de Grupos de Investigación en Sida del Fondo de Investigación Sanitaria (FIS); and the Fundación Máxímo Soriano Jiménez (Barcelona, Spain). Dr. JM Miro was a recipient of a Research Grant from the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and the Conselleria de Salut de la Generalitat de Catalunya, Barcelona (Spain).