Jeffrey L. Lennox

Raltegravir with optimized background therapy for resistant HIV-1 infection.

BACKGROUND Raltegravir (MK-0518) is an inhibitor of human immunodeficiency virus type 1 (HIV-1) integrase active against HIV-1 susceptible or resistant to older antiretroviral drugs. METHODS We conducted two identical trials in different geographic regions to evaluate the safety and efficacy of raltegravir, as compared with placebo, in combination with optimized background therapy, in patients infected with HIV-1 that has triple-class drug resistance in whom antiretroviral therapy had failed. Patients were randomly assigned to raltegravir or placebo in a 2:1 ratio. RESULTS In the combined studies, 699 of 703 randomized patients (462 and 237 in the raltegravir and placebo groups, respectively) received the study drug. Seventeen of the 699 patients (2.4%) discontinued the study before week 16. Discontinuation was related to the study treatment in 13 of these 17 patients: 7 of the 462 raltegravir recipients (1.5%) and 6 of the 237 placebo recipients (2.5%). The results of the two studies were consistent. At week 16, counting noncompletion as treatment failure, 355 of 458 raltegravir recipients (77.5%) had HIV-1 RNA levels below 400 copies per milliliter, as compared with 99 of 236 placebo recipients (41.9%, P<0.001). Suppression of HIV-1 RNA to a level below 50 copies per milliliter was achieved at week 16 in 61.8% of the raltegravir recipients, as compared with 34.7% of placebo recipients, and at week 48 in 62.1% as compared with 32.9% (P<0.001 for both comparisons). Without adjustment for the length of follow-up, cancers were detected in 3.5% of raltegravir recipients and in 1.7% of placebo recipients. The overall frequencies of drug-related adverse events were similar in the raltegravir and placebo groups. CONCLUSIONS In HIV-infected patients with limited treatment options, raltegravir plus optimized background therapy provided better viral suppression than optimized background therapy alone for at least 48 weeks. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)

Guidelines for the Management of Chronic Kidney Disease in HIV-Infected Patients: Recommendations of the HIV Medicine Association of the Infectious Diseases Society of America

Samir K. Gupta, Joseph A. Eustace, Jonathan A. Winston, Ivy I. Boydstun, Tejinder S. Ahuja, Rudolph A. Rodriguez, Karen T. Tashima, Michelle Roland, Nora Franceschini, Frank J. Palella, Jeffrey L. Lennox, Paul E. Klotman, Sharon A. Nachman, Stephen D. Hall, and Lynda A. Szczech Divisions of Infectious Diseases and Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis; Division of Nephrology, Johns Hopkins University, School of Medicine and Department of Epidemiology, Bloomberg School of Public Health, Baltimore, Maryland; Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, New York, and Division of Nephrology and Hypertension and Division of Infectious Diseases, Department of Pediatrics, State University of New York, Stony Brook; Division of Nephrology, Department of Medicine, University of Texas Medical Branch, Galveston; Division of Nephrology, Department of Medicine, San Francisco General Hospital and Positive Health Program at San Francisco General Hospital and the UCSF AIDS Research Institute, Department of Medicine, University of California at San Francisco; Division of Infectious Diseases, Department of Medicine, The Miriam Hospital, Brown Medical School, Providence, Rhode Island; Division of Nephrology and Hypertension, Department of Medicine, University of North Carolina at Chapel Hill, and Duke Clinical Research Institute and the Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, North Carolina; Division of Infectious Diseases, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; and Grady Infectious Disease Program, Division of Infectious Diseases, Department of Medicine, Emory University, Atlanta, Georgia

Subgroup and Resistance Analyses of Raltegravir for Resistant HIV-1 Infection

BACKGROUND We evaluated the efficacy of raltegravir and the development of viral resistance in two identical trials involving patients who were infected with human immunodeficiency virus type 1 (HIV-1) with triple-class drug resistance and in whom antiretroviral therapy had failed. METHODS We conducted subgroup analyses of the data from week 48 in both studies according to baseline prognostic factors. Genotyping of the integrase gene was performed in raltegravir recipients who had virologic failure. RESULTS Virologic responses to raltegravir were consistently superior to responses to placebo, regardless of the baseline values of HIV-1 RNA level; CD4 cell count; genotypic or phenotypic sensitivity score; use or nonuse of darunavir, enfuvirtide, or both in optimized background therapy; or demographic characteristics. Among patients in the two studies combined who were using both enfuvirtide and darunavir for the first time, HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 89% of raltegravir recipients and 68% of placebo recipients. HIV-1 RNA levels of less than 50 copies per milliliter were achieved in 69% and 80% of the raltegravir recipients and in 47% and 57% of the placebo recipients using either darunavir or enfuvirtide for the first time, respectively. At 48 weeks, 105 of the 462 raltegravir recipients (23%) had virologic failure. Genotyping was performed in 94 raltegravir recipients with virologic failure. Integrase mutations known to be associated with phenotypic resistance to raltegravir arose during treatment in 64 patients (68%). Forty-eight of these 64 patients (75%) had two or more resistance-associated mutations. CONCLUSIONS When combined with an optimized background regimen in both studies, a consistently favorable treatment effect of raltegravir over placebo was shown in clinically relevant subgroups of patients, including those with baseline characteristics that typically predict a poor response to antiretroviral therapy: a high HIV-1 RNA level, low CD4 cell count, and low genotypic or phenotypic sensitivity score. (ClinicalTrials.gov numbers, NCT00293267 and NCT00293254.)

Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial

BACKGROUND Use of raltegravir with optimum background therapy is effective and well tolerated in treatment-experienced patients with multidrug-resistant HIV-1 infection. We compared the safety and efficacy of raltegravir with efavirenz as part of combination antiretroviral therapy for treatment-naive patients. METHODS Patients from 67 study centres on five continents were enrolled between Sept 14, 2006, and June 5, 2008. Eligible patients were infected with HIV-1, had viral RNA (vRNA) concentration of more than 5000 copies per mL, and no baseline resistance to efavirenz, tenofovir, or emtricitabine. Patients were randomly allocated by interactive voice response system in a 1:1 ratio (double-blind) to receive 400 mg oral raltegravir twice daily or 600 mg oral efavirenz once daily, in combination with tenofovir and emtricitabine. The primary efficacy endpoint was achievement of a vRNA concentration of less than 50 copies per mL at week 48. The primary analysis was per protocol. The margin of non-inferiority was 12%. This study is registered with ClinicalTrials.gov, number NCT00369941. FINDINGS 566 patients were enrolled and randomly allocated to treatment, of whom 281 received raltegravir, 282 received efavirenz, and three were never treated. At baseline, 297 (53%) patients had more than 100 000 vRNA copies per mL and 267 (47%) had CD4 counts of 200 cells per microL or less. The main analysis (with non-completion counted as failure) showed that 86.1% (n=241 patients) of the raltegravir group and 81.9% (n=230) of the efavirenz group achieved the primary endpoint (difference 4.2%, 95% CI -1.9 to 10.3). The time to achieve such viral suppression was shorter for patients on raltegravir than on efavirenz (log-rank test p<0.0001). Significantly fewer drug-related clinical adverse events occurred in patients on raltegravir (n=124 [44.1%]) than those on efavirenz (n=217 [77.0%]; difference -32.8%, 95% CI -40.2 to -25.0, p<0.0001). Serious drug-related clinical adverse events occurred in less than 2% of patients in each drug group. INTERPRETATION Raltegravir-based combination treatment had rapid and potent antiretroviral activity, which was non-inferior to that of efavirenz at week 48. Raltegravir is a well tolerated alternative to efavirenz as part of a combination regimen against HIV-1 in treatment-naive patients. FUNDING Merck.

Correlation of Human Immunodeficiency Virus Type 1 RNA Levels in Blood and the Female Genital Tract

In this study, the correlations of human immunodeficiency virus type 1 (HIV-1) RNA levels in blood plasma, vaginal secretions, and cervical mucus of 52 HIV-1-infected women were determined. The amount of cell-free HIV-1 RNA in blood plasma was correlated with that in vaginal secretions (Spearmans rank correlation coefficient (r) = 0.64, P<.001). In both blood plasma and vaginal secretions, the amounts of cell-free and cell-associated HIV-1 RNA were highly correlated (r=0.76, P<.01 and r=0.85, P<.01, respectively). Cell-free HIV-1 RNA levels in blood plasma and vaginal secretions were negatively correlated with CD4+ T lymphocyte count (r=-0.44, P<.01 and r=-0.40, P<.01, respectively). Similar to the effect observed in blood plasma, initiation of antiretroviral therapy significantly reduced the amount of HIV-1 RNA in vaginal secretions. These findings suggest that factors that lower blood plasma virus load may also reduce the risk of perinatal and female-to-male heterosexual transmission by lowering vaginal virus load.

Raltegravir versus efavirenz regimens in treatment-naive HIV-1-infected patients: 96-week efficacy, durability, subgroup, safety, and metabolic analyses

Background:We analyzed the 96-week results in the overall population and in prespecified subgroups from the ongoing STARTMRK study of treatment-naive HIV-infected patients. Methods:Eligible patients with HIV-1 RNA (vRNA) levels >5000 copies per milliliter and without baseline resistance to efavirenz, tenofovir, or emtricitabine were randomized in a double-blind noninferiority study to receive raltegravir or efavirenz, each combined with tenofovir/emtricitabine. Results:At week 96 counting noncompleters as failures, 81% versus 79% achieved vRNA levels <50 copies per milliliter in the raltegravir and efavirenz groups, respectively [Δ (95% confidence interval) = 2% (−4 to 9), noninferiority P < 0.001]. Mean change in baseline CD4 count was 240 and 225 cells per cubic millimeter in the raltegravir and efavirenz groups, respectively [Δ (95% confidence interval) = 15 (−13 to 42)]. Treatment effects were consistent across prespecified baseline demographic and prognostic subgroups. Fewer drug-related clinical adverse events (47% versus 78%; P < 0.001) occurred in raltegravir than efavirenz recipients. Both regimens had modest effects on serum lipids and glucose levels and on body fat composition. Conclusions:When combined with tenofovir/emtricitabine in treatment-naive patients, raltegravir exhibited durable antiretroviral activity that was noninferior to the efficacy of efavirenz through 96 weeks of therapy. Subgroup analyses were generally consistent with the overall findings. Both regimens were well tolerated.

Long-Term Efficacy and Safety of Raltegravir Combined with Optimized Background Therapy in Treatment-Experienced Patients with Drug-Resistant HIV Infection: Week 96 Results of the BENCHMRK 1 and 2 Phase III Trials

BENCHMRK-1 and -2 are ongoing double-blind phase III studies of raltegravir in patients experiencing failure of antiretroviral therapy with triple-class drug-resistant human immunodeficiency virus infection. At week 96 (combined data), raltegravir (400 mg twice daily) plus optimized background therapy was generally well tolerated, with superior and durable antiretroviral and immunological efficacy, compared with optimized background therapy alone.

Benign symmetric lipomatosis associated with protease inhibitors

Unprecedented advances in the treatment of HIV-1 infection can be attributed in a large part to the use of protease inhibitors. Protease inhibitors are metabolised by the hepatic cytochrome P450 system of enzymes, and interactions at this site of metabolism are a cause of the side effects associated with these medications. Protease inhibitors can affect lipid metabolism, and glucose tolerance. We report a patient who developed unusual fatty deposits (benign symmetric lipomatosis) while on indinavir, lamivudine, and zidovudine. A 34-year-old man has been seen for HIV-1 infection as an outpatient at our clinic since May, 1995. In October 1993 he and his wife both tested positive for HIV-1. At that time he was without symptoms and his CD4 count was 285 10/L. Zidovudine was begun in November, 1993, and trimethoprim/sulfamethoxasole prophylaxis in August, 1994. Other than an episode of herpes zoster he remained well. In April and June, 1996, lamivudine and indinavir were added to his medications. In August, 1996, myalgia and weakness prompted a measurement of his creatine kinase (CK), which was elevated. Without any change in treatment, his myalgia and weakness resolved within 3 weeks, although his CK has remained elevated. At a follow up in December 1996 a “buffalo hump”—accumulation of fat in the cervical fat pad area and across the shoulders—was noted (figure). He also had fatty changes in the supraclavicular area, but no other features suggestive of Cushing’s syndrome at that time. Blood tests revealed only a minimally elevated blood glucose. Electrolytes and cholesterol were normal. A low-dose dexamethasone suppression test was normal, ruling out Cushing’s syndrome. His HIV-1 RNA viral load was undetectable, and he has continued on what has otherwise been a successful regimen for his HIV-1 infection without any worsening of fat deposition. Benign symmetric lipomatosis is an uncommon condition seen predominantly in male alcoholics. Apart from alcohol, associations have included glucose intolerance, hyperlipidemia, hyperuricemia, and polyneuropathy. Studies have implicated abnormal lipolytic responses of adipocytes to catecholamine and elevated levels of lipoprotein lipase and lipoprotein 1 . Our patient has never drunk alcohol. The temporal association between starting his medications and developing his “buffalo hump”, the effect of protease inhibitors on P450 enzymes, and the recent associations between indinavir use and glucose and lipid metabolism lead us to believe indinavir may be implicated in the development of benign symmetric lipomatosis.

HIV in body fluids during primary HIV infection: Implications for pathogenesis, treatment and public health

ObjectiveTo describe initial viral dissemination to peripheral tissues and infectious body fluids during human primary HIV infection. DesignObservational cohort study. MethodsBlood plasma, cerebrospinal fluid (CSF), seminal plasma, cervicovaginal lavage fluid and/or saliva were sampled from 17 individuals with primary HIV infection (range of time from symptoms onset to sampling, 8–70 days) and one individual with early infection (168 days). Subjects’ HIV-1 RNA levels in each fluid were compared with levels from antiretroviral-naive controls with established HIV infection. For study subjects, correlations were assessed between HIV-1 RNA levels and time from symptoms onset. Responses to antiretroviral therapy with didanosine + stavudine + nevirapine ± hydroxyurea were assessed in each compartment. ResultsHIV-1 RNA levels were highest closest to symptoms gnset in blood plasma (18 patients) and saliva (11 patients). CSF HIV-1 RNA levels (five patients) appeared lower closer to symptoms onset, although they were higher overall in primary versus established infection. Shedding into seminal plasma (eight patients) and cervicovaginal fluid (two patients) was established at levels observed in chrgnic infection within 3–5 weeks of symptoms onset. High-level seminal plasma shedding was associated with coinfection with other sexually transmitted pathogens. Virus replication was suppressed in all compartments by antiretroviral therapy. ConclusionsPeak level HIV replication is established in blood, oropharyngeal tissues and genital tract, but potentially not in CSF, by the time patients are commonly diagnosed with primary HIV infection. Antiretroviral therapy is unlikely to limit initial virus spread to most tissue compartments, but may control genital tract shedding and central nervous system expansiof in primary infection.

Randomized trial of the quantitative and functional antibody responses to a 7-valent pneumococcal conjugate vaccine and/or 23-valent polysaccharide vaccine among HIV-infected adults.

In a double-blinded, randomized trial, human immunodeficiency virus (HIV)-infected adults with > or = 200 CD4 cells/microl received placebo (PL), 7-valent conjugate, or 23-valent pneumococcal polysaccharide (PS) vaccine in one of the following two-dose combinations given 8 weeks apart: conjugate-conjugate, conjugate-polysaccharide, placebo-polysaccharide, placebo-placebo. A total of 67 persons completed the study. Neither significant increases in HIV viral load nor severe adverse reactions occurred in any group. After controlling for confounders, when compared with persons receiving placebo-polysaccharide, persons receiving conjugate-conjugate and conjugate-polysaccharide had higher antibody concentrations (serotypes 4, 6B, 9V and serotype 23F, respectively) and opsonophagocytic titers (functional antibody assay, serotypes 9V, 23F and serotypes 4, 6B, 9V, respectively) after the second dose (P<0.05). The second dose with either conjugate or polysaccharide following the first conjugate dose, however, produced no further increase in immune responses.