Homayoon Khanlou

Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48

Background:The present primary analysis of AntiRetroviral Therapy with TMC114 ExaMined In naive Subjects (ARTEMIS) compares the efficacy and safety of once-daily darunavir/ritonavir (DRV/r) with that of lopinavir/ritonavir (LPV/r) in treatment-naive patients. Methods:Patients with HIV-1 RNA at least 5000 copies/ml were stratified by HIV-1 RNA and CD4 cell count in a phase III, open-label trial, and randomized to receive DRV/r 800/100 mg qd or LPV/r 800/200 mg total daily dose (bid or qd) plus fixed-dose tenofovir and emtricitabine for 192 weeks. The primary objective was to demonstrate non-inferiority of DRV/r as compared with LPV/r in HIV-1 RNA less than 50 copies/ml per-protocol time-to-loss of virologic response at 48 weeks. Results:Six hundred and eighty-nine patients were randomized and treated; mean baseline HIV-1 RNA: 4.85 log10 copies/ml and median CD4 count: 225 cells/μl. At 48 weeks, 84% of DRV/r and 78% of LPV/r patients achieved HIV-1 RNA less than 50 copies/ml (estimated difference = 5.6 [95% confidence interval −0.1–11]%), demonstrating non-inferiority of DRV/r as compared with LPV/r (P < 0.001; per-protocol time-to-loss of virologic response). Patients with HIV-1 RNA at least 100 000 copies/ml had a significantly higher response rate with DRV/r (79%) versus LPV/r (67%; P < 0.05). Median CD4 cell count increases (non-completer = failure; cells/μl) were 137 for DRV/r and 141 for LPV/r. DRV/r had a lower incidence of possibly treatment-related grade 2–4 gastrointestinal-related adverse events (7 versus 14%) and treatment-related moderate-to-severe diarrhea (4 versus 10%) than LPV/r. Adverse events leading to discontinuation were DRV/r: 3% and LPV/r: 7%. Conclusion:DRV/r 800/100 mg qd was non-inferior to LPV/r 800/200 mg at 48 weeks, with a more favorable safety profile. Significantly higher response rates were observed with DRV/r in patients with HIV-1 RNA at least 100 000 copies/ml. DRV/r 800/100 mg offers a new effective and well tolerated once-daily, first-line treatment option for treatment-naive patients.

Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells

Gene transfer has potential as a once-only treatment that reduces viral load, preserves the immune system and avoids lifetime highly active antiretroviral therapy. This study, which is to our knowledge the first randomized, double-blind, placebo-controlled, phase 2 cell-delivered gene transfer clinical trial, was conducted in 74 HIV-1-infected adults who received a tat-vpr-specific anti-HIV ribozyme (OZ1) or placebo delivered in autologous CD34+ hematopoietic progenitor cells. There were no OZ1-related adverse events. There was no statistically significant difference in viral load between the OZ1 and placebo group at the primary end point (average at weeks 47 and 48), but time-weighted areas under the curve from weeks 40-48 and 40-100 were significantly lower in the OZ1 group. Throughout the 100 weeks, CD4+ lymphocyte counts were higher in the OZ1 group. This study indicates that cell-delivered gene transfer is safe and biologically active in individuals with HIV and can be developed as a conventional therapeutic product.

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.

Similar efficacy of raltegravir when used with or without a protease inhibitor in treatment-experienced patients.

Abstract Background: Patients with multiclass-resistant HIV-1 have limited treatment options. Raltegravir, an inhibitor of integrase, has shown excellent efficacy when used with protease inhibitors (Pis) in patients with drug-resistant HIV-1. Limited data are available however about the outcomes when using raltegravir without Pis in this population. Methods: Medical records of subjects who received raltegravir as part of the Merck EAP study 0518 were reviewed and abstracted at participating sites. Eligibility criteria included HIV positivity, age ≥16 years, limited or no treatment options due to resistance or intolerance to multiple antiretroviral regimens, detectable viremia on current treatment regimen, and documented resistance to at least one drug in each antiretroviral class (PI, NNRTI, and nucleoside analogue). Demographic, clinical, and laboratory data were collected locally using a standardized collection form. Genotypic susceptibility scores (GSS) were determined from the most recent genotypic resistance test available prior to the initiation of raltegravir. The main objective was to compare virologic results in patients who received raltegravir with a PI versus those who received raltegravir without a PI. Results: Four hundred forty-two subjects were evaluated from the respective sites in the EAP trial, of whom 340 were evaluable. The baseline mean HIV RNA was 4.6 log copies/ mL, and the mean CD4 cell count was 159 cells/μL. The median number of total and new antiretroviral agents in the background regimen was 4 and 2, respectively. Among the 254 patients who received a PI, the most common PI used was darunavir (89%). Etra-virine was commonly used in both groups: 39% of the PI group and 67% of the non-PI group. At week 12, 67% of PI patients and 64% of non-PI patients achieved HIV RNA <75 copies/mL and 85% and 86%, respectively, achieved HIV RNA <400 copies/mL GSS, which was similar in both groups at baseline, predicted achieving an HIV RNA of <400 and 75 copies/mL at week 12 (P < .05). Conclusions: In treatment-experienced patients, the combination of raltegravir with a regimen not containing a PI (used with etravirine in two-thirds of patients) had similar virologic activity when compared to more standard regimens using raltegravir with a PI. The main determinant of efficacy was the number of active drugs as measured by GSS. These data expand the potential utility of raltegravir in patients with multidrug-resistant HIV.

TMP/SMX is still the preferred empiric antibiotic for methicillin-resistant Staphylococcus aureus skin and soft tissue infection in the HIV population.

To the Editors: Within the last decade, there has been an increased incidence in methicillinresistant Staphylococcus aureus (MRSA) skin and soft tissue infections (SSTI) within the HIV-infected population. Research has identified low CD4 counts, intravenous drug use, male-to-male sexual contact, syphilis, end-stage renal disease, and recent beta-lactam antibiotic use as risk factors for MRSA SSTI in this population. Not surprisingly, recurrence of infection is high (27%) at 6-month followup. Therefore, treatment of these patients can be complicated. Skin and soft tissue infections in the general population often improve with incision and drainage alone, but patients with advanced immunosuppression and high rates of recurrence often require antibiotic therapy. Selection of empiric antibiotic therapy can be complicated in this population who frequently are exposed to trimethoprim-sulfamethoxazole for pneumocystis prophylaxis and doxycycline for treatment of chlamydia. To help determine which antibiotic should be the preferred empiric agent in MRSA SSTI, we reviewed all cases of SSTI with MRSA results by culture report in our Los Angeles–based clinics from 2005 to 2010. We studied the resistance patterns of all culture-proven MRSA SSTI from 2005–2010 (group 1) and then compared our data with the antibiogram of MRSA SSTI culture data collected in 2003–2004 (group 2) to ascertain if there has been a significant shift in the resistance pattern in the last 5 years. During 2005–2010 (group 1), we identified 152 patients (12 females) who had culture-proven MRSA SSTI. Within group 1, TMP/SMX resistance was 5%, clindamycin resistance was 35%, tetracycline resistance was 13%, and rifampin resistance was ,1%. Data from 2003 to 2004 demonstrate culture-proven MRSA SSTI in 64 patients (2 females). In this group, TMP/SMX resistance was 1.5%, clindamycin resistance was 17%, tetracycline resistance was 37.5%, and rifampin resistance was 0% (Fig. 1). During the 5-year period, our data suggest an increase of MRSA resistance to TMP/SMX, clindamycin, and rifampin. Interestingly, we did note a decrease in tetracycline resistance. Resistance rates to TMP/SMX have increased, however, it remains lower than other agents, rendering it the preferred empiric antibiotic for MRSA SSTI in HIVinfected patients currently.

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.