Shilpa Sayana

Maraviroc: a new CCR5 antagonist.

Maraviroc is a small molecule and a member of a new class of antiretroviral compounds known as CCR5 antagonists, which block R5-tropic HIV entry into CD4 cells. HIV entry into the cell requires binding to a CD4 molecule and, in the majority of cases, to a coreceptor, either chemokine coreceptor 4 (CXCR4) or 5 (CCR5). In August 2007, the US FDA approved maraviroc for use in combination with other antiretroviral agents for treatment-experienced adults infected with CCR5-tropic HIV-1 only and who have evidence of viral replication. Maraviroc prevents the virus from entering uninfected cells by blocking the CCR5 coreceptor. Maraviroc has two dose formulations (150- and 300-mg tablets) and can be taken with or without food. The dosing recommendations are based on concomitant medications due to drug interactions. It is excreted primarily in the feces, with approximately 25% via urine. The safety and efficacy of maraviroc have not been established in pregnant women or pediatric patients. Maraviroc has been shown to achieve an undetectable HIV-1 RNA level in clinically advanced, class 3 antiretroviral treatment-experienced adults with evidence of CCR5-tropic HIV-1 replication despite ongoing antiretroviral therapy. It is generally well tolerated and its development is responding to a desperate need for new classes of antiretroviral agents that can target novel steps of the HIV lifecycle and do not share crossresistance with currently available therapy.

Analysis of a switch from enfuvirtide to raltegravir in patients with undetectable viral load: efficacy and quality of life at 24 weeks.

To the Editor: Tolerability and potential for long-term treatment adherence are critical components of a successful human immunodeficiency virus (HIV) treatment regimen. Approval of newer classes of antiretroviral (ARV) medications allows new options for HIVinfected patients. Enfuvirtide (ENF) is a potent ARV medication dosed subcutaneously twice daily in treatment-experienced HIV-infected patients. In clinical trials, nearly all ENF-treated patients (97.6%) had at least 1 injection-site reaction. A total of 11 patients (3.3%) in the ENF group and 3 patients in the control group who switched to ENF (2.6%) discontinued treatment with ENF owing to injection-site reactions. Other difficulties reported were dislike of self-injection and storage of needles and injection paraphernalia. Raltegravir (RAL) is the first in a new class of integrase inhibitors that was approved by the US Food and Drug Administration (FDA) for use in treatment-experienced adult patients who have evidence of viral replication and HIV strains resistant to multiple ARV drugs. It has demonstrated potent efficacy through 48 weeks in 2 controlled studies that were conducted in clinically advanced, 3-class ARV medication, treatment-experienced adults. We conducted a study to access the virologic and quality of life effects of changing ENF to RAL in HIV-infected patients with an undetectable viral load, defined as HIV-RNA levels <50 copies/mL. This was a multicenter, open label, historical controlled study, which included patients from 6 AIDS Healthcare Foundation’s Clinics in California. Patients who were 18 years or older, who were receiving a stable ARV regimen containing ENF for >6 months, with HIV-RNA levels <50 copies/mL and no previous use of RAL or elvitegravir were asked to participate. Patients who were willing had their ARV medication changed from ENF to RAL with no other ARV medication change. Human immunodeficiency virus-1 RNA measurements and CD4 counts were performed at baseline, week 12, and week 24. A quality of life questionnaire was administered at week 12. A total of 25 patients met our inclusion criteria (24 men and 1 woman). The mean age was 49 years (range 33-64). The baseline CD4 count was 332 cells/mm (range 155-538). In all, 60% (15) of patients completed the quality of life questionnaire whose results are summarized in Table 1. All the patients (22/22) who were followed at 6 months maintained an HIV-RNA level <48 copies/ mL and an average CD4 count of 370 cells/mm (range 211-700). In all, 2 patients were lost to follow up and 1 died from head trauma. Few prior studies have shown the virologic effect of switching ENF to RAL in virologically suppressed patients. One study showed all 35 patients having maintained undetectable viral loads for several months. In another report, 18 participants on ENF for a median of 21 months discontinued this agent in favor of RAL and all maintained virologic suppression for more than 12 weeks. A larger study showed that 94% of 52 patients were able to maintain viral suppression at 12 weeks and their CD4 counts increased by an average of þ32 cells/mm In summary, our findings show that a switch from ENF to RAL in virologically suppressed patients who are highly treatment-experienced maintain both virologic and immunologic efficacy up to 24 weeks.

Meningitis Due to Hematogenous Dissemination of Community-Associated Methicillin-Resistant Staphylococcus aureus (MRSA) in a Patient With AIDS

Meningitis due to methicillin-resistant Staphylococcus aureus is a rare clinical presentation but has been well documented in postneurosurgical patients. To our knowledge, no case of methicillin-resistant Staphylococcus aureus meningitis has been previously reported in a nonneurosurgical patient with AIDS. In this case report we describe a person with AIDS who had no history of a neurosurgical procedure, shunt devices, head trauma, or recent hospitalization that presented with methicillin-resistant Staphylococcus aureus meningitis. The infection was successfully treated. Methicillin-resistant Staphylococcus aureusshould be considered in the differential of meningitis in people with AIDS.

Raltegravir: the first in a new class of integrase inhibitors for the treatment of HIV

Raltegravir (formerly known as MK-0518; Isentress®) is the first in a new class of integrase inhibitors approved for the use in treatment-experienced adult patients who have evidence of viral replication and HIV strains resistant to multiple antiretroviral agents. It is dosed twice daily with or without food. Raltegravir is a novel antiretroviral that has been shown to be well tolerated. It has demonstrated potent efficacy in the virologic suppression of HIV-1 RNA levels up to 48 weeks in two controlled studies that were conducted in clinically advanced, three-class antiretroviral, treatment-experienced adults.

An unusual pathogen for a liver abscess in a human immunodeficiency virus-infected individual.

Pyogenic liver abscesses are rarely encountered in HIV-infected patients living outside of temperate climates and are usually polymicrobial in nature, with a majority of the pathogens arising from gastrointestinal flora. We describe the second case of a liver abscess in an HIV-positive individual that was caused by methicillin-resistant Staphylococcus aureus (MRSA), most likely due to a partially treated community-acquired MRSA skin abscess. The liver abscess was successfully managed by percutaneous drainage and intravenous antibiotics. This case underlines the ubiquitous nature of community-acquired MRSA and its possible unusual presentations in immunocompromised hosts.

Efficacy and Tolerability of RAL, MVC and ETV used in combination in the treatment of highly treatment experienced HIV infected patients

Background Although the durability of antiretroviral (ARV) efficacy has improved, mainly due to better tolerability, ease of administration (adherence) and potency, some patients still encounter virological and immunological treatment failure. These patients have been on multiple regimens containing nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitor (NNRTI) and Protease Inhibitor (PI) and have become resistant to one or more of these classes. Hence, the need for salvage therapies using newly approved antiretrovirals that are NRTI, NNRTI and PI sparing is a clinical reality. Raltegravir, maraviroc and etravirine are 3 new agents with distinguished characteristics which are now available however guidelines for their use continue to evolve and none exist yet on using them all in combination. In this study we reviewed patients who were four ARV class experienced and on salvage regimens consisting of a combination of raltegravir, etravirine and maraviroc.

The use of darunavir/ritonavir as intensification in low viremic HIV-infected patients treated with boosted protease inhibitor-containing regimens.

To the Editor: Persistent low-level viremia is a precursor to the development of resistant mutations leading to overt treatment failure.Hence, the most updated US Department of Health and Human Services (DHHS) guidelines recommend that the goal of human immunodeficiency virus (HIV) treatment is to suppress HIV-RNA levels maximally and prevent further selection of resistance mutations, if possible. Trials of newer antiretroviral (ARV) agents have shown that it is possible to achieve plasma HIV-1 RNA levels below 50 copies/mL even in highly treatment-experienced patients. Darunavir (DRV) is an example of a newer ARV agent belonging to the class of protease inhibitors (PIs) with potent antiviral effect on wild type and resistant HIV virus. We hypothesize that patients with a low-level viremia while treated with ritonavir-boosted PI (PI/r), in the absence of genotypic mutations, will be able to achieve complete viral suppression with DRV/r. Patients were selected if they had been on a stable PI/r-containing regimen for at least 12 months and had >95% adherence by self-report and physician evaluation. Low viremia was defined as having HIV-RNA level >50 but <2000 copies/mL on 2 consecutive occasions within last 3 months before enrollment and no evidence of DRV genotypic mutations. DRV/r was added in place of PI/r without changing other agents. A total of 14 patients met these selection criteria. The median age was 55 years (range: 38-62) with 93% being male (n 1⁄4 13). The PI/r consisted of lopinavir/r in 6 patients, fosamprenavir/r in 4, atazanavir/r in 2, and lopinavir/saquinavir/r in 2. Ten patients were also receiving tenofovir and emtricitabine and 4 abacavir (ABC) and lamivudine (3TC). Genotypic testing in all patients did not disclose any resistant conferring mutation to DRV or other PIs. The median baseline CD4 count and HIV-RNA levels were, respectively, 345 cells/mm (7-586) and 774 copies/mL (2.9 log10; 139-1450). At week 12, the median CD4 count was increased by þ42 cells/mm and 93% of patients were <400 copies/mL (n 1⁄4 13). At week 24, the median CD4 count was 412 cells/ mm (þ69 from baseline; 29-837) with 100% of patients <400 copies/mL and 93% of patients <50 copies/mL (n 1⁄4 13; <50-250). Total cholesterol and triglycerides were 162 mg/dL (119-218) and 200 mg/dL (79-416) at baseline; 155 mg/dL (101268) and 120 mg/dL (72-280), respectively, at week 24. All patients tolerated DRV/r well and there were no grade 2 adverse events. Previous studies have shown the impact of mutational patterns in the presence of low-level viral replication. One such retrospective study was the continuous treatment with Trizivir (the fixed-dosed combination of ABC, 3TC, and zidovudine) in the presence of viral replication, which resulted in a stepwise accumulation of resistance mutations. Lafeuillade et al performed 2 genotypic tests on 22 HIVpositive patients while they were receiving a stable regimen of ARV drugs and maintaining viral loads between 50 and 1000 copies/mL.Almost 70% of the patients developed new mutations over a median of 28 months. In another retrospective analysis, the EuroSIDA cohort focused on 110 patients with HIV-RNA >400 copies/mL who continued on failing regimens for a median of 6 months. Overall, 77% of patients acquired 1 or more mutations over the study period. Although our study does not address the etiology of low-level viremia, it demonstrates that intensification with a potent agent is able to reduce detectable viremia, in all but one, indicating that this approach could be a viable option.

Use of Maraviroc-, Raltegravir-, and Etravirine-Containing Regimens in Treatment-Experienced Patients: A Case-Series Study

The development of newer agents such as raltegravir, etravirine and maraviroc has improved the perspective of viral load suppression. However, there is not enough data regarding their use together. In this study, we describe nine patients who were triple-class experienced and were on a salvage regimen consisting of a combination of raltegravir, etravirine, and maraviroc. Our results showed that this regimen is safe with no major side effect and has good virological efficacy with two-thirds of the patients achieving an undetectable viral load by 24 weeks.

Avoid a different standard of care when applying results of Development of Antiretroviral Therapy in Africa (DART) study.

This letter to the editor discusses the results of a Development of Antiretroviral Therapy in Africa (DART) study which found that little survival benefit was attained with laboratory monitoring as opposed to clinical monitoring alone in the care of HIV-infected patients. It states that the DART results suggest that a high level of health may be attained and sustained without routine laboratory monitoring and up to one-third more HIV-infected people could be treated with the money saved.

The 104 Day Report: A Successful Intervention of Improving Patient Retention

Integrated results of 2 phase 3 studies comparing tigecy-cline and levofloxacin in community-acquired pneumonia. and safety of tigecycline compared with van-comycin or linezolid for treatment of serious infections with methicillin-resistant Staphylococcus aureus or vancomycin-resistant en-terococci: a phase 3, multicentre, double-blind, randomized study. A phase 3, open-label, noncomparative study of tigecycline in the treatment of patients with selected serious infections due to resistant gram-negative organisms including Entero-bacter species, Acinetobacter baumannii and Klebsiella pneumoniae. and body fluid concentrations of tigecycline after a single 100-mg dose. Staphylococcus aureus bacteremia: recurrence and the impact of antibiotic treatment in a prospective multicenter study. A, et al. Infectious Diseases Society of America/ American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. To the Editor—We appreciate the interest in the article and the comments. As was mentioned in the letter by Dr Tarchini [1], our article [2] specified very clearly the limitations to the analysis, and we agree that these limitations should be applied to all post hoc analyses. Several additional points require clarification. First, the analysis was not a meta-analysis; it was a pooled analysis of secondary bacteremia in tigecyclines approved indications. Second , we believe that the comments by Dr Tarchini [1] on the quality of the data and the interpretation of the data are not accurate. The purpose of the randomized, double-blind clinical trials was to determine the safety and efficacy of tigecycline empirical therapy with appropriate and approved comparators for each given indication. Given the serum pharmacoki-netic data of tigecycline, the purpose of the pooled analysis was to determine the safety and efficacy of tigecycline empirical therapy in the subset of subjects with secondary bacteremia within the approved indications. The advantages and disadvantages of individual antibiotic choices for definitive therapy were not the primary aim of the clinical trials or the pooled analysis. In addition, the comment by Dr Tar-chini [1] regarding empirical levofloxacin therapy for the treatment of community-acquired pneumonia is not accurate. Lev-ofloxacin is approved for 7–14 days therapy at the 500-mg dose, and this was the recommended dose at the time the trials [3, 4] were designed and initiated. We believe that our statement regarding the similarity in cure rates between empirical ti-gecycline therapy and appropriate and approved empirical comparative therapy in subjects with secondary bacteremia is accurate [2]. Acknowledgments Potential conflicts of interest. All authors are or were employed by the manufacturer of tige-cycline (Wyeth/Pfizer). …