Anton Pozniak

Efficacy of short-term monotherapy with maraviroc, a new CCR5 antagonist, in patients infected with HIV-1

We assessed the efficacy and safety of 10-d monotherapy with the orally administered CCR5 antagonist maraviroc in 63 HIV-1-positive individuals prescreened for the absence of CXCR4-using virus. Maximum reduction in viral load occurred at a median of 10–15 d, with a mean reduction of ≥1.6 log10 copies/ml at all twice daily doses ≥100 mg. These results provide proof of concept that CCR5 antagonism is a viable antiretroviral therapeutic approach.

Treatment of tuberculosis in HIV-infected persons in the era of highly active antiretroviral therapy

Objective To assess the risks and benefits of administering highly active antiretroviral therapy (HAART) during the treatment of tuberculosis (TB) in HIV-infected patients. Design and methods HIV-1 patients presenting to 12 HIV centres in Greater London and south-east England with culture-proven TB were identified from January 1996 to June 1999. Case-notes were reviewed retrospectively. Results Patients (n = 188) were severely immunocompromised with a median CD4 cell count at TB diagnosis of 90 × 106 cells/l (IQR: 30–180). At presentation, 85% (n = 159) were not taking antiretrovirals. A total of 45% commenced HAART during TB treatment, which was associated with significant reductions in viral load, AIDS-defining illness (ADI) [3.5 versus 24.5%; relative risk (RR) = 0.14] and mortality. Only nine of 91 (10%) patients with a CD4 count > 100 × 106 cells/l at TB diagnosis experienced a further ADI, whereas 18 of 92 (20%) patients with a CD4 count < 100 × 106 cells/l developed this complication. Adverse events (AE) occurred in 99 (54%) of 183 patients, one-third of whom changed or interrupted HIV and/or TB medication. The majority of AE occurred within the first 2 months, with peripheral neuropathy (21%), rash (17%) and gastrointestinal upset (10%) occurring most commonly. Conclusions Many physicians delay HAART in patients presenting with TB because of pill burden, drug/drug interactions and toxicity. Although the use of HAART led to significant reductions in viral load, ADI and mortality, co-infected patients commonly experienced AE leading to interruptions in TB/HIV therapy. We therefore recommend starting HAART early for patients with advanced HIV disease (CD4 < 100 × 106 cells/l) and deferring HAART until the continuation phase of TB therapy (i.e. after 2 months) for patients who are clinically stable (CD4 > 100 × 106 cells/l).

Emergence of CXCR4-Using Human Immunodeficiency Virus Type 1 (HIV-1) Variants in a Minority of HIV-1-Infected Patients following Treatment with the CCR5 Antagonist Maraviroc Is from a Pretreatment CXCR4-Using Virus Reservoir

ABSTRACT Antagonists of the human immunodeficiency virus type 1 (HIV-1) coreceptor, CCR5, are being developed as the first anti-HIV agents acting on a host cell target. We monitored the coreceptor tropism of circulating virus, screened at baseline for coreceptor tropism, in 64 HIV-1-infected patients who received maraviroc (MVC, UK-427,857) as monotherapy for 10 days. Sixty-two patients harbored CCR5-tropic virus at baseline and had a posttreatment phenotype result. Circulating virus remained CCR5 tropic in 60/62 patients, 51 of whom experienced an HIV RNA reduction from baseline of >1 log10 copies/ml, indicating that CXCR4-using variants were not rapidly selected despite CCR5-specific drug pressure. In two patients, viral load declined during treatment and CXCR4-using virus was detected at day 11. No pretreatment factor predicted the emergence of CXCR4-tropic virus during maraviroc therapy in these two patients. Phylogenetic analysis of envelope (Env) clones from pre- and posttreatment time points indicated that the CXCR4-using variants probably emerged by outgrowth of a pretreatment CXCR4-using reservoir, rather than via coreceptor switch of a CCR5-tropic clone under selection pressure from maraviroc. Phylogenetic analysis was also performed on Env clones from a third patient harboring CXCR4-using virus prior to treatment. This patient was enrolled due to a sample labeling error. Although this patient experienced no overall reduction in viral load in response to treatment, the CCR5-tropic components of the circulating virus did appear to be suppressed while receiving maraviroc as monotherapy. Importantly, in all three patients, circulating virus reverted to predominantly CCR5 tropic following cessation of maraviroc.

Effect of transmitted drug resistance on virological and immunological response to initial combination antiretroviral therapy for HIV (EuroCoord-CHAIN joint project): a European multicohort study

BACKGROUND The effect of transmitted drug resistance (TDR) on first-line combination antiretroviral therapy (cART) for HIV-1 needs further study to inform choice of optimum drug regimens. We investigated the effect of TDR on outcome in the first year of cART within a large European collaboration. METHODS HIV-infected patients of any age were included if they started cART (at least three antiretroviral drugs) for the first time after Jan 1, 1998, and were antiretroviral naive and had at least one sample for a genotypic test taken before the start of cART. We used the WHO drug resistance list and the Stanford algorithm to classify patients into three resistance categories: no TDR, at least one mutation and fully-active cART, or at least one mutation and resistant to at least one prescribed drug. Virological failure was defined as time to the first of two consecutive viral load measurements over 500 copies per mL after 6 months of therapy. FINDINGS Of 10,056 patients from 25 cohorts, 9102 (90·5%) had HIV without TDR, 475 (4·7%) had at least one mutation but received fully-active cART, and 479 (4·8%) had at least one mutation and resistance to at least one drug. Cumulative Kaplan-Meier estimates for virological failure at 12 months were 4·2% (95% CI 3·8-4·7) for patients in the no TDR group, 4·7% (2·9-7·5) for those in the TDR and fully-active cART group, and 15·1% (11·9-19·0) for those in the TDR and resistant group (log-rank p<0·0001). The hazard ratio for the difference in virological failure between patients with TDR and resistance to at least one drug and those without TDR was 3·13 (95% CI 2·33-4·20, p<0·0001). The hazard ratio for the difference between patients with TDR receiving fully-active cART and patients without TDR was 1·47 (95% CI 0·19-2·38, p=0·12). In stratified analysis, the hazard ratio for the risk of virological failure in patients with TDR who received fully-active cART that included a non-nucleoside reverse transcriptase inhibitor (NNRTI) compared with those without TDR was 2·0 (95% CI 0·9-4·7, p=0·093). INTERPRETATION These findings confirm present treatment guidelines for HIV, which state that the initial treatment choice should be based on resistance testing in treatment-naive patients. FUNDING European Communitys Seventh Framework Programme FP7/2007-2013 and Gilead.

Efficacy of Tenofovir Disoproxil Fumarate in Antiretroviral Therapy-Naive and -Experienced Patients Coinfected with HIV-1 and Hepatitis B Virus

BACKGROUND Coinfection with human immunodeficiency virus type 1 (HIV-1) increases the risk of hepatitis B virus (HBV)-associated progressive liver disease. Lamivudine has potent activity against both HIV-1 and HBV; however, lamivudine-resistance mutations in HBV frequently develop. METHODS Substudies of the safety and efficacy of tenofovir disoproxil fumarate (tenofovir DF) for patients coinfected with HIV and HBV were undertaken within 2 phase 3 randomized controlled trials involving antiretroviral therapy-experienced (study 907) and -naive (study 903) HIV-infected populations. Inclusion criteria were detection of hepatitis B surface antigen, an HBV DNA level >106 copies/mL at baseline, and HBV DNA specimens available at week 24 (study 907) and week 48 (study 903). RESULTS In study 907, the mean decrease in HBV DNA was 4.9 log(10), after 24 weeks, for 10 patients randomized to receive tenofovir DF, compared with a mean increase of 1.2 log(10) for 2 patients randomized to receive placebo (P=.041). The mean decrease in HBV DNA during tenofovir DF treatment was similar for patients with wild-type (5.3 log(10)) and lamivudine-resistant (4.6 log(10)) HBV strains. In study 903, the mean decrease in HBV DNA was 3.0 log(10), after 48 weeks, for 6 patients randomized to receive lamivudine, compared with 4.7 log(10) for 5 patients randomized to receive lamivudine and tenofovir DF (P=.055). Four patients developed tyrosine-methionine-aspartate-aspartate mutations, all in the lamivudine-only treatment arm. CONCLUSION Tenofovir DF has potent anti-HBV efficacy in antiretroviral therapy-experienced and -naive individuals coinfected with HIV and HBV.

European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of HIV-infected adults

A working group of the European AIDS Clinical Society (EACS) have developed these guidelines for European clinicians to help them in the treatment of adults with HIV infection. This third version of the guidelines includes, as new topics, the assessment of patients at initial and subsequent clinic visits as well as post‐exposure prophylaxis. A revision of the 2005 guidelines based on current data includes changes in the sections on primary HIV infection, when to initiate therapy, which drug combinations are preferred as initial combination regimens for antiretroviral‐naïve patients, how to manage virological failure and the treatment of HIV during pregnancy.

Tenofovir disoproxil fumarate, emtricitabine, and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive patients: 144-Week analysis

Background:As antiretroviral regimens for the treatment of HIV infection improve, trials providing data on long-term follow-up are increasingly important. Methods:A regimen of tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and efavirenz (EFV) demonstrated superior virologic, immunologic and morphologic effects compared with a regimen of fixed-dose zidovudine/lamivudine (ZDV/3TC) and EFV through 96 weeks in a randomized open-label trial. After 96 weeks, patients on TDF + FTC transitioned to fixed-dose combination TDF/FTC. Results:Through 144 weeks, significantly more patients in the TDF/FTC arm reached and maintained an HIV RNA level <400 copies/mL (71% receiving TDF/FTC and EFV vs. 58% receiving ZDV/3TC and EFV; P = 0.004), with a trend toward greater CD4 cell increase in the TDF/FTC arm (312 vs. 271 cells/mm3; P = 0.09). Over 144 weeks of follow-up, more patients in the ZDV/3TC arm discontinued therapy because of adverse events (11% vs. 5%; P = 0.01) and no patients discontinued because of renal events. Patients in the ZDV/3TC arm had significantly less limb fat than patients in the TDF/FTC arm (5.4 vs. 7.9 kg; P < 0.001) at 144 weeks. Conclusions:Cumulative results from 3 years of follow-up suggest that a regimen of TDF/FTC and EFV demonstrates superior durability of viral load suppression and an improved safety and morphologic profile compared with ZDV/3TC and EFV.

Tenofovir Disoproxil Fumarate in Nucleoside-Resistant HIV-1 Infection: A Randomized Trial

Context Resistance to antiretroviral drugs is a leading cause of treatment failure in HIV-1infected patients. Contribution In this multicenter, double-blind trial, 552 treatment-experienced patients with detectable RNA levels despite continuing antiretroviral therapy were randomly assigned to receive tenofovir DF (a nucleotide analogue) or placebo. At 6 months, patients given tenofovir DF had greater reductions in HIV-1 RNA levels than those given placebo. Nearly 15% of patients in both groups had clinical adverse events, such as severe diarrhea, pain, or depression. Implications In HIV-infected patients with suboptimal viral suppression, adding tenofovir DF to ongoing antiretroviral therapy reduces viral loads. The Editors Combination antiretroviral therapy has decreased mortality rates for patients with HIV-1 infection (1, 2). Suppression of HIV-1 viral load has been shown to be highly predictive of slower clinical disease progression (3). However, the clinical utility of a combination antiretroviral regimen typically wanes, often because of one or more factors such as drug resistance or poor adherence (4). These factors are even more important for patients who have previously used antiretroviral drugs. This difficult-to-treat population has limited treatment options and often experiences drug-related adverse effects due to previous antiretroviral therapy regimens (5-7). Given these limitations, novel potent agents that combine ease of dosing with favorable safety and resistance profiles are needed to increase the long-term durability of combination antiretroviral therapy (8, 9). Simplifying HIV treatment regimens using once-daily antiretroviral drugs may improve adherence and therapeutic outcomes (10, 11). Tenofovir disoproxil fumarate (tenofovir DF) is an oral prodrug of tenofovir, a novel, acyclic nucleotide analogue with in vitro activity against HIV-1 and HIV-2 (12, 13). Unlike nucleoside analogues, tenofovir is active in both active and resting lymphoid cells and macrophages (13). In rhesus macaques acutely infected with simian immunodeficiency virus, tenofovir administered as monotherapy 24 hours after inoculation eradicated viral DNA from lymph nodes, plasma, and leukocytes (14). Tenofovir has also demonstrated in vitro activity against wild-type and lamivudine-resistant hepatitis B virus (15). In a 186-patient phase II dose-ranging study, Schooley and colleagues (16) demonstrated the potency and favorable safety profile of tenofovir DF, 300 mg, highlighting its potential for further study in larger phase III trials. Tenofovir has a favorable resistance profile with activity against most nucleoside analogueresistant viruses and infrequent (3%) emergence of the K65R resistance mutation through 96 weeks (17-21). Our study was designed to confirm the antiviral efficacy and safety of tenofovir DF compared with placebo in treatment-experienced patients who had detectable HIV-1 RNA levels despite combination antiretroviral therapy. Methods Study Sample Institutional review boards at all study sites approved the study protocol and informed consent statements. Recruitment began in October 1999 and continued until June 2000 at 75 HIV clinics in western Europe, North America, and Australia. All patients gave written informed consent. Patients 18 to 65 years of age were eligible if they had received antiretroviral therapy (four agents or fewer) for at least 8 weeks before randomization and had stable plasma HIV-1 RNA levels of 400 to 10 000 copies/mL on the Roche Amplicor HIV-1 Monitor UltraSensitive test, version 1.0 (Roche Diagnostics, Branchburg, New Jersey). The lower limit of quantification for this test was 50 copies/mL. We placed no entry restrictions on CD4 cell count. Additional inclusion criteria were serum creatinine concentration of 133 mol/L or less ( 1.5 mg/dL), calculated creatinine clearance (using the CockcroftGault formula [22]) of at least 1.00 mL/s ( 60 mL/min), absolute neutrophil count of at least 1.000 109 cells/L, platelet count of at least 50.0 109 cells/L, hemoglobin level of at least 80 g/L, total bilirubin level of 26 mol/L or less ( 1.5 mg/dL), serum phosphorus level of at least 0.71 mmol/L ( 2.2 mg/dL), alanine aminotransferase level less than 108 U/L, aspartate aminotransferase level less than 90 U/L, negative results on a serum pregnancy test for women of childbearing potential, and life expectancy of more than 1 year. We excluded patients who had previously participated in clinical trials with intravenous tenofovir, tenofovir DF, or adefovir dipivoxil; had been immunized within 30 days of baseline; had an active AIDS-defining condition within 30 days of baseline; or were receiving aminoglycoside antibiotics, amphotericin B, cidofovir, cisplatin, foscarnet, intravenous pentamidine, vancomycin, ganciclovir, systemic chemotherapeutic agents, oral corticosteroids, probenecid, or other investigational agents on an ongoing basis. Patients who were receiving their first antiretroviral regimen were not excluded. We assessed 976 patients for eligibility and randomly assigned 552 to study groups (Figure). Four hundred twenty-four patients were excluded. Of the 380 who did not meet inclusion criteria, the most common reason (n = 269) was HIV-1 RNA levels outside the range of 400 to 10 000 copies/mL. Among the remaining 44 patients, 22 elected not to participate in the study and the other 22 were excluded because of investigator decision, concomitant participation in other investigational studies, screening after the cutoff date for enrollment, incomplete laboratory values, lack of follow-up, or family emergency. No statistical analyses were performed for patients who were not randomly assigned to a study group. Figure. Recruitment and disposition flow chart. Design Through an interactive voice response system that centralized patient randomization, Interactive Clinical Technologies, Inc. (San Francisco, California), generated the random allocation sequence, assigned patients to their treatment groups, and blinded kit numbers to conceal the allocation sequence. Patients were stratified according to HIV-1 RNA level (<5000 copies/mL or 5000 copies/mL), CD4 cell count (<0.2 109 cells/L or 0.2 109 cells/L), and number of antiretroviral drugs taken before study entry (fewer than four or at least four). Patients were then randomly assigned in a 2-to-1 ratio to add tenofovir DF, 300 mg, or identical-appearing placebo to their existing antiretroviral regimen. Randomization was not stratified by study center. Changes to the background regimen were discouraged during the first 24 weeks. After week 24, all patients received open-label tenofovir DF for the remainder of the 48-week study. As predefined in both the study protocol and the statistical analysis plan, the single end point for primary efficacy was the time-weighted average change in HIV-1 RNA level from baseline to week 24. Secondary efficacy end points included the proportion of patients with HIV-1 RNA levels of 50 copies/mL or less and 400 copies/mL or less at weeks 24 and 48, the time-weighted average change in HIV-1 RNA level from baseline to week 48, and CD4 cell count at weeks 24 and 48. Adherence to treatment was measured by using pill counts at each study visit, but pill counts were not formally analyzed and drug concentrations were not measured during routine study visits. Approximately half of the patients (n = 274) were randomly assigned to a virologic genotyping substudy at baseline. HIV-1 reverse transcriptase nucleotides 1 to 1200 and all of the HIV-1 protease gene were sequenced by following the reverse transcriptase polymerase chain reaction from plasma HIV-1 RNA (Vircogen, Virco, Mechelen, Belgium). All plasma HIV-1 samples that were obtained at baseline, at week 24 or 48, or at early study termination and had more than 50 copies of HIV-1 RNA per mL were analyzed in a blinded fashion. A polymerase chain reaction product could not be obtained from 21 patients at baseline (14 in the tenofovir DF group, 7 in the placebo group). Plasma HIV-1 RNA was insufficient for genotypic analysis in 58 patients at week 24 (43 patients in the tenofovir DF group, 15 in the placebo group) and 129 patients at week 48. Assessments The incidences of grade 3 or 4 clinical adverse events or laboratory abnormalities were evaluated as safety end points. At each postbaseline study visit (weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48), the investigator assessed and recorded all adverse events found during history and physical examination as well as laboratory toxicities found on chemical and hematologic tests and urinalysis, including date of onset and resolution, severity, relationship to study drug, outcome, and action taken with study medication. Severity was recorded and graded according to the modified severity grading for adult adverse experiences outlined by the National Institutes of Allergy and Infectious Diseases, Division of AIDS. Plasma levels of HIV-1 RNA and CD4 cell counts were measured at all study visits except weeks 28, 36, and 44. Statistical Analysis Data were analyzed for the intention-to-treat sample and the as-treated sample. The intention-to-treat sample included all enrolled patients who received at least one dose of study medication and was the primary sample for analyses of efficacy. The as-treated sample included patients who received at least one dose of study medication but excluded all data obtained after permanent discontinuation of assigned study medication or addition of other antiretroviral medication. The safety analysis sample included all patients who received at least one dose of study medication. As the primary efficacy end point, the time-weighted average change in HIV-1 RNA level from baseline to week 24 represents the difference between the time-weighted average postbaseline values and values at baseline. This difference is defined as follows (23, 24). If the area under the curve (AUC) at week 24 (

Efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: 24-week results of POWER 1.

Background:The ongoing phase IIb POWER 1 (TMC114-C213) trial is designed to assess efficacy and safety of the protease inhibitor (PI) TMC114 (darunavir) in treatment-experienced HIV-1-infected patients. Design:This randomized, partially blinded, 24-week dose-finding study compared efficacy and safety of four doses of TMC114 plus low-dose ritonavir (TMC114/r) with investigator-selected control PI(s) (CPI[s]). Methods:Patients with one or more primary PI mutation and HIV RNA > 1000 copies/ml received optimized background therapy, plus TMC114/r 400/100 mg once daily, 800/100 mg once daily, 400/100 mg twice daily or 600/100 mg twice daily, or CPI(s). The primary endpoint (intent-to-treat) compared proportions of patients achieving viral load reduction ≥ 1.0 log10 copies/ml from baseline. Results:In total, 318 patients were treated. Baseline mean viral load was 4.48 log10 copies/ml; median CD4 cell count was 179 cells/μl. In the CPI arm 62% of patients discontinued (virological failure: 54%); 10% of TMC114/r patients discontinued. More TMC114/r (69–77%) than CPI patients (25%) reached the primary endpoint (P < 0.001); 43–53% of TMC114/r patients and 18% of the CPI arm achieved viral load < 50 copies/ml (P < 0.001). TMC114/r demonstrated greater mean CD4 cell count increases versus CPI(s) (68–124 versus 20 cells/μl; P < 0.05). TMC114/r 600/100 mg twice daily demonstrated the highest virological and immunological responses. Adverse event incidence was similar between treatments; headache and diarrhoea were more common with CPI(s). Conclusions:TMC114/r demonstrated statistically higher 24-week virological response rates and CD4 cell count increases than CPI(s). TMC114/r 600/100 mg twice daily has received regulatory approval in treatment-experienced patients.

UK Guideline for the use of post-exposure prophylaxis for HIV following sexual exposure

We present the updated British Association for Sexual Health and HIV (BASHH) guidelines for post-exposure prophylaxis (PEPSE) to HIV. This document includes a review of the current data to support the use of PEPSE, considers how to calculate the risks of infection after a potential exposure, and provides recommendations on when PEPSE would and would not be considered. We review which agents to use for PEPSE including the potential for drug-drug interactions and make recommendations for monitoring individuals receiving PEPSE. Other areas included are the possible impact on sexual behaviour, cost-effectiveness and issues relating to service provision. Throughout the document, consideration is given to the place of PEPSE within the broader context of HIV prevention strategies and sexual health.