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Serologic evaluation of human immunodeficiency virus type 1-infected individuals from Argentina and the United States indicates a similar distribution of subgroup B isolates
(1995-02) Warren, Ronald; Wong, Michael; Melcher, Gregory; Blatt, Stephen; Cahn, Pedro; Perez, Héctor; Zapiola, Inés; Bouzas, María Belén; Muchinik, Guillermo; Anderson, Stephanie; Kennedy, Ronald
This study examined serum specimens from HIV-1 infected individuals from Argentina (n = 50) and the United States (n = 38) for antibody reactivity to a panel of V3-based synthetic peptides. Serum specimens were further analyzed for the ability to neutralize laboratory and clinical isolates of HIV-1 in vitro. Patterns of antibody reactivity to these V3 peptides, together with neutralizing activity, indicated that infected individuals from both Argentina and the US have been exposed to HIV-1 isolates belonging to subgroup B. Serum specimens from the United States (37 males and 1 female) were obtained from military personnel and their dependents. Of these patients, 35 were asymptomatic and 3 were symptomatic. Specimens from Argentina were obtained from HIV-1-infected individuals examined in Buenos Aires, Argentina (37 males and 13 females). Half of the infected individuals from Argentina were symptomatic. Serum specimens were screened for antibody reactivity to HIV-1 gp160 synthetic peptides by an enzyme-linked immunosorbent assay. Examination of V3 peptide recognition indicated that a higher percentage of Argentinean serum specimens reacted with peptide RP189 than serum specimens from the United States (34% and 5%, respectively). A higher percentage of serum specimens from the United States reacted with peptide RP135 (LAI) than was observed with serum specimens from Argentina (47% vs. 16%, respectively). Neutralization assays again indicated a similar pattern of antibody reactivity with serum specimens from infected individuals from Argentina and the United States. Nucleotide sequence analysis of clinical isolates has demonstrated that the HIV-1 subgroup B is predominant in the United States. Serologic reactivity to V3-based peptides in this study suggests that isolates commonly found in the US (i.e., MN, SF2, and NY-5) are also frequently observed in Argentina. These results suggest that there is similar distribution of HIV-1 subgroup B isolates among infected individuals from Argentina and the United States.
Comparative studies of two-times-daily versus three-times-daily indinavir in combination with zidovudine and lamivudine
(2000-09) Haas, David; Arathoon, Eduardo; Thompson, Melanie; de Jesus Pedro, Rogiero; Gallant, Joel E; Uip, David E; Currier, Judith; Noriega, Miguel; Lewi, David; Uribe, Patricia; Benetucci, Jorge; Cahn, Pedro; Paar, David; White, Clinton Jr; Collier, Ann; Ramirez-Ronda, Carlos; Harvey, Charlotte; Chung, Mi-ok; Mehrotra, Devan; Chodakewitz, Jeffrey; Nguyen, Bach-Yen
Objectives: To compare the efficacy and safety of two-times-daily versus three-times-daily indinavir in combination with zidovudine and lamivudine. Design: Two multicenter, open-label, randomized 24-week studies. Methods: Adults HIV-1 infection, HIV-1 RNA greater than 10000 copies/ml, and no prior lamivudine or protease inhibitor therapy were eligible. In a pilot study (Study A), patients received indinavir at 800 mg every 8 h, 1000 mg every 12 h, or 1200 mg every 12 h. In a subsequent study (Study B), patients received indinavir at 800 mg every 8 h or 1200 mg every 12 h. All subjects received zidovudine (300 mg) and lamivudine (150 mg) every 12 h. An intent-to-treat analysis was used. Results: In Study A, which enrolled 88 patients, neither HIV-1 RNA nor CD4 cell responses differed significantly between treatment groups at 24 weeks when corrected for multiple comparisons. Study B enrolled 433 patients, but was prematurely discontinued when interim analysis suggested greater efficacy of three-times-daily indinavir. Of the first 87 patients reaching week 24, HIV-1 RNA was less than 400 copies/ml in 91% receiving three-times-daily versus 64% receiving two-times-daily indinavir (P < 0.01). Conclusion: Three-times-daily indinavir appears more efficacious than two-times-daily dosing when administered with zidovudine and lamivudine. Two-times-daily indinavir dosing should only be considered in situations characterized by favorable pharmacokinetic drug-drug interactions.
Higher Rate of Toxicity With No Increased Efficacy When Hydroxyurea Is Added to a Regimen of Stavudine Plus Didanosine and Nevirapine in Primary HIV Infection
(2002-04-01) Zala, Carlos; Salomon, Horacio; Ochoa, Claudia; Kijak, Gustavo; Federico, Andrea; Perez, Héctor; Julio SG, Montaner; Cahn, Pedro
Summary: Twenty-four subjects presenting at a single treatment center with primary HIV infection were enrolled in a pilot study aimed to establish the possible role of hydroxyurea in this setting. Study participants were randomly assigned to receive or not to receive hydroxyurea in addition to stavudine (d4T) plus didanosine (ddI) and nevirapine (NVP). Seventy-five percent of patients without hydroxyurea had plasma HIV RNA below 50 copies/mL at 48 weeks by both intention-to-treat (ITT) and on-treatment (OT) analysis in comparison with 50% (ITT) and 67% (OT) of patients with hydroxyurea (p > .1). A median increase of >200 cells/mm3 was observed from baseline to week 48 whether or not hydroxyurea was included in the regimen. Overall, in 12 patients treated with hydroxyurea, 33 adverse events were reported versus 19 reported for 12 patients who did not receive hydroxyurea (p < .05). Our results suggest that that adding hydroxyurea to a regimen of d4T plus ddI and NVP increases toxicity without improving the antiviral effect.
Transient Fungemia Caused by an Amphotericin B-Resistant Isolate of Candida haemulonii
(2002-06-01) Rodero, Laura; Cuenca-Estrella, Manuel; Córdoba, Susana; Cahn, Pedro; Davel, Graciela; Kaufman, Sara; Guelfand, Liliana; Rodríguez-Tudela, Juan L
A bloodstream infection due to Candida haemulonii afflicting a patient with fever and a medical history of megaloblastic anemia is reported. The clinical isolate was misidentified by the API 20C and VITEK identification systems. The results of susceptibility tests showed that the MIC of amphotericin B for C. haemulonii was 4 μg/ml. Additional susceptibility testing procedures based on the use of antibiotic medium 3 and Iso-Sensitest broth were performed, and killing curves were determined. Two collection strains of C. haemulonii were employed as controls. The three isolates exhibited resistance to amphotericin B in vitro regardless of the antifungal susceptibility testing method employed. In addition, the MICs of fluconazole for the three isolates were high. Further studies are needed in order to ascertain whether this species exhibits innate or acquired resistance to amphotericin B and other antifungal agents. Candida haemulonii (Van Uden & Kolipinski) S. A. Meyer & Yarrow (Yarrow and Meyer 1978) (syn. Torulopsis haemulonii) is a yeast species that has been reported in the scales of animals and in seawater and has been recently associated with an epidemic disease afflicting laboratory animals (Ornithodoros moubata) in the Czech Republic (5, 10, 11). This fungus is also involved in human infections such as onychia, ulcers of the feet or legs, and candidemia (10). Identification of C. haemulonii is difficult because it is phenotypically very similar to Candida famata (teleomorph, Debaryomyces hansenii) and Candida guilliermondii (teleomorph, Pichia guilliermondii), although it can be distinguished by its inability to assimilate cellobiose and its negative or weak assimilation of raffinose (8, 10). In addition, commercial yeast identification systems have failed to identify C. haemulonii isolates (16). Lehmann et al. studied 25 clinical isolates of C. haemulonii and described two genetically distinct groups within the species (group I and group II) on the basis of isoenzyme profiles, DNA reassociations, and physiological characteristics (9, 10, 16). No differences in clinical associations between the groups were described, but it was determined that C. haemulonii constitutes a species complex. The susceptibility pattern of C. haemulonii is unknown, but an anecdotal report has suggested that it could be resistant to amphotericin B (AMB) and other antifungal agents (4). Here, we describe a case of transient fungemia due to a C. haemulonii strain which exhibited resistance to AMB and fluconazole in vitro. Killing curves were determined and additional susceptibility tests were performed to assess the activity of AMB against the isolate.
A Randomized Clinical Trial Comparing Nelfinavir Or Nevirapine Associated to Zidovudine/Lamivudine in HIV-Infected Naive Patients (The Combine Study)
(2002-07) Podzamczer, Daniel; Ferrer, Elena; Consiglio, Ezequiel; Mariá Gatell, José; Perez, Pepa; Perez, José Luis; Luna, Elena; González, Alicia; Pedrol, Enric; Lozano, Luisa; Ocaña, Imma; Llibre, Josep María; Casiró, Arnaldo; Aranda, Miquel; Barrufet, Pilar; Martínez-Lacasa, Javier; Miró, José María; Badía, Xavier; Casado, Alfonso; Lupo, Sergio; Cahn, Pedro; Maños, Manel; Estela, Jordi; The Combine Study Team (Members Listed In Appendix)
Background Non-nucleoside reverse transcriptase inhibitor-containing regimens may be a valid alternative to protease inhibitor-containing regimens for initial antiretroviral therapy, but to date few studies comparing these two strategies have been performed. Objective To evaluate the efficacy and safety of nelfinavir or nevirapine associated to zidovudine/lamivudine in HIV-infected naive patients. Design Randomized, open-label, multicentre trial. Setting Twelve centres in Spain (9) and Argentina (3). Patients One hundred and forty-two HIV-infected naive patients without AIDS. Interventions Patients received combivir (zidovudine 300 mg/lamivudine 150 mg, twice-daily) plus either nelfinavir (1250 mg) twice-daily (zidovudine/lamivudine/nelfinavir, n=70) or nevirapine (200 mg) twice-daily (zidovudine/lamivudine/nevirapine, n=72), and were followed for 12 months. The primary endpoint was the proportion of patients with a plasma HIV-1 RNA (pVL) of less than 200 copies/ml by PCR at 12 months. pVL of less than 20 copies/ml (PCR), changes in CD4 counts, clinical progression and adverse events were also evaluated. Efficacy was assessed using intent-to-treat (ITT) (missing=failure) and on-treatment analysis. Results At 12 months in the ITT analysis the proportion of patients with pVL below 200 copies/ml was 60% (95% CI 48.5–71.5) in the zidovudine/lamivudine/nelfinavir arm and 75% (95% CI 65–85) in the zidovudine/lamivudine/nevirapine arm (P=0.06), and the proportion below 20 copies/ml was 50% (95% CI 38.3–61.7) and 65% (95% CI 54.2–76.2), respectively (P=0.06). No differences were found when comparing the subgroup of patients with baseline pVL of more than 100 000 copies/ml. A gain of +173 and +162 CD4 cells/mm3, respectively, was observed. Zidovudine/lamivudine/nelfinavir was discontinued in 21% of patients, and zidovudine/lamivudine/ nevirapine in 25%, due to toxicity (P>0.2). Conclusions Our results suggest that zidovudine/ lamivudine/nevirapine is at least as effective as zidovudine/lamivudine/nelfinavir as first-line therapy for HIV disease.
Origin of human immunodeficiency virus type 1 quasispecies emerging after antiretroviral treatment interruption in patients with therapeutic failure
(2002-07-15) Kijak, Gustavo H; Simon, Viviana; Balfe, Peter; Vanderhoeven, Jeroen; Pampuro, Sandra E; Zala, Carlos; Ochoa, Claudia; Cahn, Pedro; Markowitz, Martin; Salomon, Horacio
The emergence of antiretroviral (ARV) drug-resistant human immunodeficiency virus type 1 (HIV-1) quasispecies is a major cause of treatment failure. These variants are usually replaced by drug-sensitive ones when the selective pressure of the drugs is removed, as the former have reduced fitness in a drug-free environment. This was the rationale for the design of structured ARV treatment interruption (STI) studies for the management of HIV-1 patients with treatment failure. We have studied the origin of drug-sensitive HIV-1 quasispecies emerging after STI in patients with treatment failure due to ARV drug resistance. Plasma and peripheral blood mononuclear cell samples were obtained the day of treatment interruption (day 0) and 30 and 60 days afterwards. HIV-1 pol and env were partially amplified, cloned, and sequenced. At day 60 drug-resistant variants were replaced by completely or partially sensitive quasispecies. Phylogenetic analyses of pol revealed that drug-sensitive variants emerging after STI were not related to their immediate temporal ancestors but formed a separate cluster, demonstrating that STI leads to the recrudescence and reemergence of a sequestrated viral population rather than leading to the back mutation of drug-resistant forms. No evidence for concomitant changes in viral tropism was seen, as deduced from env sequences. This study demonstrates the important role that the reemergence of quasispecies plays in HIV-1 population dynamics and points out the difficulties that may be found when recycling ARV therapies with patients with treatment failure. The different variants of human immunodeficiency virus type 1 (HIV-1) present in infected individuals have been described as quasispecies of related but distinct viruses; this plasticity of phenotype allows the virus to occupy a large adaptive landscape from which novel phenotypes may readily emerge (7, 17, 23). These variants are generated continuously due to the high replication rate of HIV-1 (50), the high frequency of recombination among viral genomes (4), and the lack of proofreading activity of the viral reverse transcriptase (RT) (41). When the selective pressure of antiretroviral (ARV) therapy is exerted on such a population, drug-resistant mutants may emerge and consequently lead to treatment failure (7, 37). The emergence of such viral variants has been extensively described and is found even in the setting of highly active ARV therapies (11, 39, 46). When this selective pressure is removed, the emergence of drug-sensitive quasispecies may be expected, as they would be predicted to have a higher fitness in a drug-free environment (9, 15, 19, 20, 22, 25, 34, 40, 42, 43). This rationale led to the many structured treatment interruption (STI) studies carried out on patients with treatment failure and multidrug-resistant viruses (10, 12, 16, 26, 45, 59). In those cohorts, a rise in plasma viral load and a concomitant fall in CD4+ cell count was observed after treatment interruption; in approximately half of the patients, drug susceptibility shifted from resistant to sensitive. However, the origin of these drug-sensitive quasispecies which emerged after STI has not been clearly defined. Understanding the mechanisms responsible for the observed changes in HIV-1 drug resistance and in viral replication after STI will provide a greater insight into HIV-1 evolution and will help define future therapeutic strategies for patients suffering treatment failure. The objective of this work was to determine the origin of drug-sensitive quasispecies arising after STI. New drug-sensitive HIV variants may be the result of point mutations (“back mutations”) in the drug-resistant quasispecies circulating immediately before STI, or they may be reemerging ancestral viral variants that had circulated before the drug-resistant viruses associated with treatment failure arose (and which had been sequestrated or suppressed during therapy). In addition we assessed whether the increase in viral load and decrease in CD4+ cell count observed after STI was associated with a change in the biological phenotype of the virus from non-syncytium-inducing/CCR5-tropic to syncytium-inducing/CXCR4-tropic. Like STI, this latter phenotype has been associated with faster replication, more rapid decline in CD4 numbers, and disease progression (6, 8, 21, 28, 56). We were able to show that viral quasispecies replicating after treatment interruption were not related to its immediate temporal ancestor but formed a separate cluster, demonstrating that STI leads to the recrudescence and reemergence of a sequestrated viral population rather than the back mutation of drug-resistant forms. No evidence for concomitant changes in viral tropism was seen. (The present study constitutes a part of Gustavo H. Kijak's doctoral work at the University of Buenos Aires.)
Time to act: global apathy towards HIV/AIDS is a crime against humanity
(2002-11) Hogg, Robert; Cahn, Pedro; Katabira, Elly; Lange, Joep; Samuel, NM; O'Shaughnessy, Michael; Vella, Stefano; Wainberg, Mark; Montaner, Julio
“There are some people who say that in Africa, people will not be able to take these drugs because they cannot tell time. I may not have a watch, but I can assure you that since I started taking my triple therapy in August last year, I haven't missed one dose.” Fred Minandi, a farmer from Malawi
Diagnosis and treatment of latent tuberculosis infection in liver transplant recipients in an endemic area
(2002-11-27) Benito, Natividad; Sued, Omar; Moreno, Asunción; Horcajada, Juan P; González, Julià; Navasa, Miquel; Rimola, Antoni
Background. Treatment of latent tuberculosis infection (LTBI) with isoniazid is recommended for transplant recipients with positive tuberculin skin test (TST). However, TST could be an imperfect identifier of LTBI in this population. In addition, the risk of isoniazid hepatotoxicity could be high in liver transplant recipients (LTR). A retrospective cohort study was performed to evaluate the diagnosis and treatment of LTBI in LTR. Methods. Charts of all 547 patients who received primary liver transplantation at a University Hospital in Spain between 1988 and 1998 were reviewed. Results. TST was performed in 373 patients (71%) before transplantation. The result was positive in 89 (24%). The median follow-up after transplantation was 49 months. None of the TST-positive patients developed tuberculosis (TB), but 5 out of 284 patients with negative TST (1.76%) had active TB (P =0.6). Twenty-three patients received isoniazid as treatment of LTBI according to the decision of the attending physician. None of these patients developed TB, but 4 of them (17%) presented isoniazid hepatotoxicity. Among patients who did not receive isoniazid, 2 out of 21 (9.52%) with radiologic previous TB developed active TB versus 0.44% (2/452) among the remaining patients (relative risk [RR], 27.8, 95% CI, 3.2–147). Conclusions. Treatment of LTBI with isoniazid can not be recommended to LTR on the basis of a positive TST because it is an imperfect identifier of patients at risk of TB. LTR with radiologic features of previous TB are at higher risk of posttransplant active TB. Isoniazid-related hepatotoxicity is more frequent among LTR than in the general population. One of the most controversial issues in the field of infectious diseases in transplant recipients is the approach to tuberculosis (TB), and most especially the treatment of latent tuberculosis infection (LTBI) in liver transplant recipients (LTR). Treatment of LTBI is effective in preventing TB disease in individuals who have a positive tuberculin skin test (TST) and who are at high risk for developing TB (1). Solid organ transplantation is associated with an increased risk of LTBI progression towards active TB. Thus, general recommendations include the administration of isoniazid to TST-positive patients with organ transplants (2,3). However, there is no consensus regarding the appropriate treatment of LTBI in these patients (4,5). On the one hand, TST could be an imperfect identifier of patients with LTBI because up to 80% of transplant candidates may be anergic (6–8). On the other hand, the risk of active disease in liver transplant patients with positive TST remains unknown. Case series and reports suggest that isoniazid treatment of LTBI is effective for transplant recipients, but this has not been demonstrated in a controlled trial (7). In addition, the efficacy of isoniazid treatment of LTBI must be considered against the risk of hepatotoxicity. It has been suggested that the risk of hepatotoxicity could be greater than the benefit of isoniazid therapy in LTR with positive TST and no other risk factors for TB (6,9–14). Nevertheless, the incidence of isoniazid hepatotoxicity in LTR is not well known (14,15). The objective of this study was to evaluate the diagnosis and treatment of LTBI with isoniazid in a large group of LTR from an endemic geographical area.
Venous and Arterial Blood Lactate in HIV-Infected Patients
(2002-12) Zala, Carlos; Harris, Marianne; Ochoa, Claudia; Tocci, Mariel; Quercia, Romina; Mittelman, Graciela; Graciela, Héctor; Cahn, Pedro; Montaner, Julio SG
Hyperlactataemia is increasingly recognised as a complication of nucleoside analogue-based antiretroviral therapy [1–5]. There is, however, some debate about the accuracy of peripheral venous blood lactate levels and whether these adequately reflect arterial lactate levels. This correlation has been demonstrated in the non-HIV, emergency medicine literature [6,7], but has not been studied in HIV patients receiving antiretroviral therapy. Therefore, we undertook the present study to compare venous versus arterial lactate levels in HIV patients who had consistently high random venous lactate while receiving chronic stavudine-based antiretroviral therapy.
Tuberculosis and HIV: A Partnership Against the Most Vulnerable
(2003) Cahn, Pedro; Perez, Hector; Ben, Graciela; Ochoa, Claudia
Tuberculosis and HIV: A Partnership Against the Most Vulnerable
Forty-eight-week evaluation of lopinavir/ritonavir, a new protease inhibitor, in human immunodeficiency virus-infected children
(2003-03) Sáez-Llorens, Xavier; Violari, Avyi; Deetz, Carl O; Rode, Richard; Gomez, Perry; Handelsman, Edward; Pelton, Stephen; Ramilo, Octavio; Cahn, Pedro; Chadwick, Ellen; Allen, Upton; Arpadi, Stephen; Castrejón, Maria Mercedes; Heuser, Renee S; Kempf, Dale J; Bertz, Richard J; Hsu, Ann F; Bernstein, Barry; Renz, Cheryl L; Sun, Eugene
Background. Lopinavir/ritonavir has demonstrated antiviral activity in the HIV-infected adult. Subjects. The objective of this study was to investigate a liquid coformulation of lopinavir/ritonavir, in combination with reverse transcriptase inhibitors, in HIV-infected children. Methods. One hundred antiretroviral (ARV)-naive and ARV-experienced, nonnucleoside reverse transcriptase inhibitor-naive children between 6 months and 12 years of age participated in this Phase I/II, open label, multicenter trial. Subjects initially received either 230/57.5 mg/m2 or 300/75 mg/m2 lopinavir/ritonavir twice daily; ARV-naive subjects also received stavudine and lamivudine, whereas ARV-experienced subjects also received nevirapine and one or two nucleoside reverse transcriptase inhibitors. Lopinavir/ritonavir pharmacokinetics, safety and efficacy were evaluated. Results. All subjects were escalated to the 300/75 mg/m2 twice daily dose based on results from an interim pharmacokinetic and safety evaluation. The pharmacokinetics of lopinavir did not appear to be dependent on age when dosing was based on body surface area but were decreased on coadministration with nevirapine. Overall 79% of subjects had HIV RNA levels <400 copies/ml at Week 48 (intent-to-treat: missing = failure). Mean increases in absolute and relative (percent) CD4 counts from baseline to Week 48 were observed in both ARV-naive subjects (404 cells/mm3; 10.3%) and ARV-experienced subjects (284 cells/mm3; 5.9%). Only one subject prematurely discontinued the study because of a study drug-related adverse event. Conclusions. The liquid coformulation of lopinavir/ritonavir demonstrated durable antiviral activity and was safe and well-tolerated after 48 weeks of treatment in HIV-infected children.
Continued indinavir versus switching to indinavir/ritonavir in HIV-infected patients with suppressed viral load
(2003-04-11) Arnaiz, Juan A; Mallolas, Josep; Podzamczer, Daniel; Gerstoft, Jan; Lundgren, Jens D; Cahn, Pedro; Fätkenheuer, Gerd; D'Arminio-Monforte, Antonella; Casiró, Arnaldo; Reiss, Peter; Burger, David M; Stek, Michael; Gatell, Jose
Objective: To compare continued indinavir (IDV) 8-hourly (q8h) with switching to indinavir/ritonavir (IDV/RTV) 12-hourly (q12h) in HIV-positive patients having suppressed viral load with IDV q8h plus two nucleoside reverse transcriptase inhibitors (NRTI). Design: Multicentre, international, randomized, open-label study enrolling HIV-1 infected patients on IDV 800 mg q8h plus two NRTI with CD4 cell counts > or = 100 x 106/l and plasma HIV RNA < 500 copies/ml for > or = 3 months. Methods: Patients were randomized to continue on the same regimen or to switch to IDV plus liquid RTV (IDV/RTV 800 mg/100 mg q12h). Primary endpoint was the proportion of patients remaining < 500 copies/ml at 48 weeks. Results: A total of 323 patients (IDV/RTV, 162; IDV, 161) were evaluable. At 48 weeks, the proportions of patients with plasma HIV RNA < 500 copies/ml were 93%, 88% and 58% in the IDV/RTV arm versus 92% (P = 1), 86% (P = 0.87) and 74% (P = 0.003) in the IDV arm using on-treatment (OT) and intent-to-treat (ITT) [switches included (ITT, S = I) and switches = failure (ITT, S = F)] analyses respectively. Mean increase in CD4 cell count was 88 x 106/cells/l (IDV/RTV arm) and 60 x 106 cells/l (IDV arm) (P = 0.08). More patients discontinued study medication due to adverse events in the IDV/RTV arm than in the IDV arm (P < 0.001). Conclusions: Equivalence of continuing IDV q8h versus switching to IDV/RTV (liquid) q12h in suppressed stable patients was demonstrated by OT and ITT S = I analyses. However, the IDV q8h arm performed better when discontinuations were classified as failures. IDV/RTV q12h can be convenient and equally effective for patients able to tolerate it
Randomized, Controlled Study of the Effects of a Short Course of Prednisone on the Incidence of Rash Associated With Nevirapine in Patients Infected With HIV-1
(2003-05-01) Montaner, Julio S.G; Cahn, Pedro; Zala, Carlos; Casssetti, Lidia; Losso, Marcelo; Hall, David B; Wruck, Jan; McDonough, Marita; Gigliotti, Maria; Robinson, Patrick A; The 1100.1286 Study Team
Objective: To examine the effect of 2 weeks of treatment with prednisone on the incidence of nevirapine-associated rash in HIV-1-infected patients receiving combination antiretroviral therapy. Methods: This was a 24-week, prospective, randomized, open-label, international study. Patients were randomized to receive nevirapine plus open-label prednisone (40 mg once daily for 14 days) (n = 69) or nevirapine alone (n = 69). All patients received at least two other antiretroviral drugs. Nevirapine was administered at the lead-in dosage of 200 mg once daily. After the initial 2 weeks of the study, the nevirapine dosage was increased to 200 mg twice daily. Results: During the first 6 weeks of treatment, rash was not reduced in the patients who received prednisone: prednisone treatment group, 23 (33%)/69; nonprednisone treatment group, 13 (19%)/69 (one-tailed Fisher exact test for prednisone reducing the incidence of rash, p = .984). There tended to be more severe rashes (7% versus 1%, respectively) and more therapy discontinuations due to rash (16% versus 9%, respectively) in the prednisone treatment group than in the nonprednisone treatment group. Risk factors for rash included higher pretreatment CD4 cell count, lower HIV-1 RNA level, female sex, and higher trough nevirapine concentrations. The prednisone treatment group had a marked increase in the median CD4 cell count in the first 2 weeks, which stabilized at a level similar to that in the nonprednisone treatment group. HIV-1 RNA responses were similar between the two groups. Treatment-naive patients had similar decreases in plasma HIV-1 RNA levels at week 24: approximately 2.3 log10 copies/mL. Conclusions: This study demonstrated that 2 weeks of concomitant therapy with prednisone does not decrease the occurrence of nevirapine-associated rash. The use of prednisone is not recommended to prevent rash in patients receiving nevirapine. Prednisone administration had no adverse effects on the virological responses or on CD4 cell count changes at 24 weeks.
Randomized Trial to Evaluate Indinavir/Ritonavir versus Saquinavir/Ritonavir in Human Immunodeficiency Virus Type 1–Infected Patients: The MaxCmin1 Trial
(2003-09-01) Dragsted, Ulrik Bak; Gerstoft, Jan; Pedersen, Court; Peters, Barry; Duran, Adriana; Obel, Niels; Castagna, Antonella; Cahn, Pedro; Clumeck, Nathan; Bruun, Johan N; Benetucci, Jorge; Hill, Andrew; Cassetti, Isabel; Vernazza, Pietro; Youle, Mike; Fox, Zoe; MaxCmin1 Trial Group
This trial assessed the rate of virological failure at 48 weeks in adult human immunodeficiency virus (HIV) type 1–infected patients assigned indinavir/ritonavir (Idv/Rtv; 800/100 mg 2 times daily) or saquinavir/ritonavir (Sqv/Rtv; 1000/100 mg 2 times daily) in an open-label, randomized (1:1), multicenter, phase 4 design. Three hundred six patients began the assigned treatment. At 48 weeks, virological failure was seen in 43 (27%) of 158 and 37 (25%) of 148 patients in the Idv/Rtv and Sqv/Rtv arms, respectively. The time to virological failure did not differ between study arms (P=.76). When switching from randomized treatment was counted as failure, this was seen in 78 of 158 patients in the Idv/Rtv arm, versus 51 of 148 patients in the Sqv/Rtv arm (P=.009). A switch from the randomized treatment occurred in 64 (41%) of 158 patients in the Idv/Rtv arm, versus 40 (27%) of 148 patients in the Sqv/Rtv arm (P=.013). Sixty-four percent of the switches occurred because of adverse events. A greater number of treatment-limiting adverse events were observed in the Idv/Rtv arm, relative to the Sqv/Rtv arm. In conclusion, Rtv-boosed Sqv and Idv were found to have comparable antiretroviral effects in the doses studied
Dose-ranging, randomized, clinical trial of atazanavir with lamivudine and stavudine in antiretroviral-naive subjects
(2003-12-05) Murphy, Robert L; Sanne, Ian; Cahn, Pedro; Phanuphak, Praphan; Percival, Lisa; Kelleher, Thomas; Giordano, Michael
Objective: To compare the efficiency and safety of atazanavir and nelfinavir in antiretroviral-naive patients. Design: Randomization to atazanavir 400 mg or 600 mg once daily; nelfinavir 1250 mg twice a day, plus lamivudine and stavudine. Methods: A blinded (to the atazanavir dose), 48-week trial in patients with HIV-1 RNA ≥ 2000 copies/ml, CD4 cell count ≥ 100 × 106cells/l. Primary end-point: change in HIV-1 RNA from baseline at 48 weeks. Secondary end-point: subjects with HIV-1 RNA < 400, and < 50 copies/ml, CD4 cell count changes, adverse events. Results: The 467 randomized subjects had comparable baseline characteristics across treatments. With atazanavir 400 mg, 600 mg and nelfinavir, respectively, mean changes in HIV-1 RNA (log10 copies/ml) from baseline to 48 weeks were −2.51, −2.58, −2.31; HIV-1 RNA < 400 copies/ml [intent-to-treat population (ITT), non-completion = failure (NC = F)], 64%, 67%, 53%; HIV-1 RNA < 50 copies/ml (ITT NC = F), 35%, 36%, 34%; mean CD4 cell count increased comparably at 48 weeks (234 × 106, 243 × 106, 211 × 106cells/l). Adverse events were similar across treatments with the exception of diarrhea (more frequent with nelfinavir) and jaundice (more frequent with atazanavir). Mean changes from baseline to 48 weeks were: fasting low density lipoprotein cholesterol, +5.2%, +7.1% and +23.2% (at 56 weeks) and fasting triglycerides (48 weeks), +7.2%, +7.6% and +49.5%, in the atazanavir 400 mg, 600 mg, and nelfinavir groups, respectively (P < 0.01, atazanavir versus nelfinavir). Conclusions: Atazanavir is a potent, safe, well tolerated, and effective once-daily protease inhibitor with low pill burden (two capsules/day). Lipid changes with atazanavir were significantly less than with nelfinavir, however, clinical significance of these finding in terms of decreased cardiovascular risk is unknown.
Predictors of adherence and virologic outcome in HIV-infected patients treated with abacavir- or indinavir-based triple combination HAART also containing lamivudine/zidovudine
(2004) Cahn, Pedro; Vibhagool, Asda; Schechter, Mauro; Soto-Ramirez, Leopoldo; Carosi, Giampiero; Smaill, Fraser; Jordan, James C.; Pharo, Carol E.; Thomas, Nancy E.; Steel, Harry M.
Objectives: To compare dosing convenience and adherence with abacavir (ABC) 300 mg plus a fixed-dose lamivudine 150 mg/zidovudine 300 mg combination tablet (COM) twice daily versus indinavir (IDV) plus COM twice daily in treatment-naïve, HIV-1-infected adults; and to evaluate the association among difficulty taking antiretroviral regimens, adherence, and virologic efficacy. Methods: An open-label, randomized, multicenter, international study compared the COM/ABC and IDV/COM regimens with respect to self-reported adherence and regimen convenience over 48 weeks. Logistic regression analysis (LRA) was done on a patient sub-sample from both groups to evaluate predictors of adherence and virologic response at last time-point on randomized therapy (LTORT). Results: The study population was diverse with respect to ethnicity (38% Asian, 27% Hispanic, 28% white, 3% black, 4% other) and gender (39% women, 61% men). Baseline median HIV-1 RNA was 4.80 log(10) copies/mL and CD4+ cell count was 315 cells/mm(3). Of 329 patients who were randomized and received treatment, 315 (96%) provided adherence data. Significantly more patients in the ABC/COM group than in the IDV/COM group reported > or = 95% adherence to therapy (76 vs 58%, p < 0.001) and no difficulty in taking their regimen (91 vs 61%, p < 0.001). In both groups, the highest probability of HIV-1 RNA < 400 copies/mL occurred when median adherence was > or = 95%. The probability of HIV-1 RNA < 400 copies/mL declined more rapidly in the IDV/COM group as adherence rates decreased. LRA showed that no difficulty taking any of the drugs in the regimen, ABC/COM treatment group, and male gender were independent significant predictors of > or = 95% adherence (p < 0.05). Median adherence and baseline HIV-1 RNA were significant predictors of HIV-1 RNA < 400 copies/mL (p < 0.05). Conclusions: Patients reported greater ease of use and superior adherence to ABC/COM than IDV/COM. Patient-reported difficulty taking drugs in a regimen was predictive of reduced adherence, and both of the latter factors were predictive of poorer virologic outcome. Adherence levels of > or = 95% in both treatment groups maximized the probability of patients achieving an HIV-1 RNA < 400 copies/mL.
Emtricitabine: A new nucleoside analogue for once-daily antiretroviral therapy
(2004) Cahn, Pedro
Highly active antiretroviral therapy has resulted in a dramatic decline in morbidity and mortality among patients infected with HIV. Nevertheless, this success has to be considered in the context of the current challenges and needs in this field. Adherence, toxicity, potency and resistance are still matters of intense research, which need to improve in order to overcome the current limitations of available drugs. Regarding needs, the improvement of convenience, tolerability and pharmacokinetics run in parallel with toxicity reduction, improvement of activity (both for wild-type and resistant virus), penetration into viral reservoirs and exploitation of new targets. The Food and Drug Administration approved emtricitabine in July 2003 for use in combination with other antiretroviral agents in adults with HIV-1 infection. Approval was based on the results of two Phase III clinical trials. The first was a double-blind study comparing the safety and efficacy of emtricitabine + didanosine + efavirenz to stavudine + didanosine + efavirenz as initial treatment in individuals who had not previously received antiretroviral therapy. At 24 and 48 weeks, patients receiving emtricitabine had significantly higher rates of virological suppression and greater increases in CD4+ counts than stavudine recipients. The second study was an open-label trial in treatment-experienced patients with HIV RNA < 400 copies/ml on a lamivudine-containing regimen in combination with either stavudine or zidovudine and either a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor for at least 12 weeks. Patients were randomised either to continue lamivudine (150 mg b.i.d.) or to switch to emtricitabine 200 mg o.d. while maintaining the same background medications. In this study, the proportion of patients whose viral loads remained suppressed at the < 400 and < 50 copies/ml levels were similar in the two treatment groups. Potency, tolerability, convenient dosing and a low rate of side effects are some of the main characteristics of this new drug.
Atazanavir—A Once-daily HIV Protease Inhibitor That Does Not Cause Dyslipidemia in Newly Treated Patients: Results from Two Randomized Clinical Trials
(2004) Cahn, Pedro; Gatell, Jose; Squires, Kathleen; Percival, Lisa D; Piliero, Peter J; Sanne, Ian A; Shelton, Sarah; Lazzarin, Adriano; Odeshoo, Linda; Kelleher, Thomas D; Thiry, Alexandra; Giordano, Michael D; Schnittman, Stephen M
Protease inhibitor (PI) treatment can result in dyslipidemia in a significant proportion of patients. Atazanavir (ATV) is a once-daily PI that has not been associated with clinically relevant increases in total cholesterol (TC), fasting low-density lipoprotein cholesterol (LDL-C), or fasting triglyceride (TG) concentrations. The objectives of this paper were to evaluate lipid profiles in untreated patients, and investigate the frequency and severity of dyslipidemia in the same individuals after treatment with ATV or nelfinavir (NFV) for 48 weeks. Two multinational, randomized, active-controlled, blinded trials compared the safety and efficacy of ATV and NFV in combination with two nucleoside reverse transcriptase inhibitors (NRTIs) in antiretroviral (ARV)-naive patients. Serum lipid concentrations were analyzed in patients who had available measurements both at baseline and at week 48. Patients who had missing data at either time point were not included. Lipid levels remained within baseline ranges at week 48 with ATV treatment, whereas clinically relevant elevations in TC, fasting LDL-C, and fasting TG concentrations occurred with NFV treatment. Mean changes from pre-treatment baseline in fasting LDL-C ranged from -6 percent to +6 percent in the ATV-treatment groups, and from +27 percent to +31 percent in the NFV-treatment groups. After 48 weeks, there was a substantive increase in the proportion of NFV-treated patients who would be recommended for lipid-lowering treatment by National Cholesterol Education Program (NCEP) guidelines, whereas a lesser proportion of ATV-treated patients would be recommended for lipid-lowering treatment. Atazanavir does not lead to dyslipidemia in ARV-naive patients, and may limit the need for lipid-lowering strategies to reduce the risk of cardiovascular disease.
Coinfection: Helicobacter pylori/Human Immunodeficiency Virus
(2004) Olmos, Maria; Araya, Valeria; Pskorz, Enrique; Quesada, Elvio C.; Concetti, Hugo; Perez, Hector; Cahn, Pedro
To compare H. pylori infection prevalence and gastric mucosa damage in HIV-infected and non-HIV-infected patients, gastric biopsies were systematically taken in 209 individuals who underwent upper Gl endoscopy (102 HIV-infected and 107 non-HIV-infected). H. pylori was found in 42 (41.1%) HIV-infected patients and in 53 (49.5%) non-HIV patients (P = 0.22, chi2 = 1.47, NS). In HIV-positive patients infected with H. pylori the mean CD4 count was higher than in HIV-positive patients without H. pylori (364 and 228 cells/mm3, respectively; P = 0.0001). H. pylori gastritis was more severe in the HIV-positive group (chi2 = 15.02, P = 0.0001). The frequency of H. pylori in gastric mucosa in HIV-infected and non-HIV patients was similar. HIV-infected patients with H. pylori had a higher mean CD4 count than HIV-infected individuals without H. pylori. Gastric lesions associated with H. pylori were more severe in the HIV-positive population.
Triple nucleoside treatment with abacavir plus the lamivudine/zidovudine combination tablet (COM) compared to indinavir/COM in antiretroviral therapy-naïve adults: Results of a 48-week open-label, equivalence trial (CNA3014)
(2004) Vibhagool, Asda; Cahn, Pedro; Schechter, Mauro; Smaill, Fraser; Soto-Ramirez, Leopoldo; Carosi, Giampiero; Montroni, Marco; Pharo, Carol E.; Jordan, James C.; Thomas, Nancy E.; Pearce, Grant
Objective: An equivalence (non-inferiority) trial comparing antiviral response, tolerability, and adherence with a triple nucleoside regimen containing abacavir 300 mg (ABC) plus a lamivudine 150-mg/zidovudine 300-mg combination tablet (COM) twice daily vs. a regimen containing the protease inhibitor indinavir (IDV) 800 mg three times daily plus COM twice daily (IDV/COM) in antiretroviral-naïve, HIV-infected patients. Methods: Adult patients with plasma HIV-1 RNA levels ≥ 5000 copies/mL and CD4+ cell counts ≥ 100 cells/mm3 were randomized to receive open-label ABC/COM (n = 169) or IDV/COM (n = 173) for 48 weeks. The intent-to-treat (ITT) population was the primary population evaluated. ITT: switch/missing equals failure (ITT: S/M = F) and as-treated (AT) analyses were used for assessing the proportion of patients achieving plasma HIV-1 RNA level < 400 and < 50 copies/mL at each clinic visit. In the ITT: S/M = F analysis, patients who switched treatment or had missing values were considered treatment failures; the AT analysis examined virologic data only while patients received study treatment. ABC/COM was considered equivalent (non-inferior) to IDV/COM if the lower limit of the 95% confidence intervals (CIs) about the difference in proportions of ABC/COM- vs. IDV/COM-treated patients attaining plasma HIV-1 RNA < 400 copies/mL exceeded –15% at week 48. Results: The study population was diverse with respect to ethnicity (38% Asian, 27% Hispanic, 28% white, 3% black, 4% other) and gender (39% women, 61% men). Baseline median HIV-1 RNA was 4.80 log10 copies/mL and CD4+ cell count was 315 cells/mm3. ABC/COM met the criterion of equivalence to IDV/COM. In the ITT: S/M = F analysis at Week 48, a greater proportion of ABC/COM-treated patients achieved HIV-1 RNA < 400 copies/mL (66% [109/164] vs. 50% [82/165]; treatment difference 16.6%, 95% CI (6.0, 27.2), p = 0.002) and HIV-1 RNA < 50 copies/mL (60% [99/164] vs. 50% [83/165]; treatment difference 9.6%, 95% CI [–1.1, 20.2]), whereas the AT analysis showed similar proportions achieving these endpoints (< 400 copies/mL: 85 vs. 83%; < 50 copies/mL: 79 vs 81%). Comparable proportions of patients with screening HIV-1 RNA values > 100 000 copies/mL achieved HIV-1 RNA < 400 copies/mL (ABC/COM: 60% [35/58]; IDV/COM: 51% [33/65]; treatment difference 9.6%, 95% CI [–7.9, 27.1]; ITT: S/M = F analysis). A significantly greater proportion taking ABC/COM were ≥ 95% adherent (72% [109/151] vs. 45% [70/154] with IDV/COM, p < 0.001). Median increases from baseline in CD4+ cell counts were similar in the two treatment groups (+148 vs. +152 cells/mm3). Significantly more patients on IDV/COM reported drug-related adverse events (87% [142/165] vs. 65% [108/164] with ABC/COM, p < 0.001), similar proportions discontinued treatment due to adverse events (13 vs. 10%), and a slightly greater proportion in the ABC/COM group reported serious adverse events (13 vs. 8%). About half of the latter comprised suspected ABC-related hypersensitivity reactions (overall rate, 6%). Most adverse events were gastrointestinal in nature in both treatment groups. Conclusion: ABC/COM was at least equivalent to IDV/COM over 48 weeks in the treatment of antiretroviral-naïve patients. ABC/COM was associated with a significantly higher adherence rate and lower incidence of drug-related adverse events than IDV/COM. The study was limited in that it was not powered to determine equivalence of treatments within high vs. low viral load strata, adherence was not monitored electronically, and bias could not be ruled out due to the open-label study design.

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