Simon Portsmouth

Deep V3 Sequencing for HIV Type 1 Tropism in Treatment-Naive Patients: A Reanalysis of the MERIT Trial of Maraviroc

BACKGROUND Deep sequencing is a highly sensitive technique that can detect and quantify the proportion of non-R5 human immunodeficiency virus (HIV) variants, including small minorities, that may emerge and cause virologic failure in patients who receive maraviroc-containing regimens. We retrospectively tested the ability of deep sequencing to predict response to a maraviroc-containing regimen in the Maraviroc versus Efavirenz in Treatment-Naive Patients (MERIT) trial. Results were compared with those obtained using the Enhanced Sensitivity Trofile Assay (ESTA), which is widely used in clinical practice. METHODS Screening plasma samples from treatment-naive patients who received maraviroc and efavirenz in the MERIT trial were assessed. Samples were extracted, and the V3 region of HIV type 1 glycoprotein 120 was amplified in triplicate and combined in equal quantities before sequencing on a Roche/454 Genome Sequencer-FLX (n = 859). Tropism was inferred from third variable (V3) sequences, with samples classified as non-R5 if ≥2% of the viral population scored ≤3.5 using geno2pheno. RESULTS Deep sequencing distinguished between responders and nonresponders to maraviroc. Among patients identified as having R5-HIV by deep sequencing, 67% of maraviroc recipients and 69% of efavirenz recipients had a plasma viral load <50 copies/mL at week 48, similar to the ESTA results: 68% and 68%, respectively. CONCLUSIONS Reanalysis of the MERIT trial using deep V3 loop sequencing indicates that, had patients originally been screened using this method, the maraviroc arm would have likely been found to be noninferior to the efavirenz arm.

Population-based sequencing of the V3-loop can predict the virological response to maraviroc in treatment-naive patients of the MERIT trial.

Background:MERIT was a randomized trial comparing maraviroc (MVC) + Combivir versus efavirenz (EFV) + Combivir in drug-naive patients screened as having R5 HIV-1 by the original Trofile assay (OTA). We retrospectively evaluated treatment response after rescreening for viral tropism using population-based V3-loop sequencing. Methods:HIV env V3-loop was amplified in triplicate using reverse transcriptase–polymerase chain reaction from stored screening plasma and sequenced. Automated base calling was performed using custom software (RECall) and tropism inferred by geno2pheno (5.75% false-positive rate). Tropism results by genotype were compared with those of OTA and Enhanced Sensitivity Trofile assay (ESTA), where all results were available (n = 876). Results:Approximately 8% of patients screened as having R5 virus by OTA were classified as having non-R5 virus by V3-loop genotyping. These patients were less likely to have early or sustained week-48 treatment response to MVC, but not EFV. When restricted to patients with R5 virus by genotype, reanalysis of the primary study endpoint (plasma viral load <50 copies/mL at week 48) showed noninferiority of MVC twice daily to EFV (67% vs. 68%). Rescreening by genotype and ESTA had 84% concordance; patients receiving MVC twice daily rescreened as having R5 virus had greater than 1 log10 copies per milliliter decrease in viral load over those rescreened as having non-R5 virus. Where genotype and ESTA screening results were discordant outcomes were similar. Conclusions:The exclusion of ∼8% of patients with CXCR4-using virus by population-based sequencing would likely have resulted in noninferior responses in the MVC twice-daily and EFV arms. Rescreening by ESTA and population-based sequencing predicted similar virological response.

Etiology and natural history of neutropenia in human immunodeficiency virus disease : A prospective study

The objective of this prospective, observational study was to define the natural history of neutropenia in human immunodeficiency virus (HIV) disease. Eighty-seven consecutive patients developing neutropenia (absolute neutrophil count [ANC], <1000 cells/mm(3)) were recruited and closely followed for the duration of the episode. Episodes lasted a median of 13 days, with a mean ANC nadir of 660 cells/mm(3). Presumed or proven infection occurred in 12 (17%) of 71 evaluable subjects, and culture-proven infection occurred only in 6 (8%) of 71. Most of the episodes of neutropenia were brief, mild to moderate in nadir, and self-limiting without complications. Myelosuppressive therapies were implicated in almost all episodes. Serious infections occurred infrequently and were associated with low ANC nadirs but not with duration of the neutropenic episode. Low CD4(+) cell counts also increased the risk of infection complicating an episode of neutropenia.

Increased duration of viral suppression is associated with lower viral rebound rates in patients with previous treatment failures.

Objective:We investigated whether the rate of viral rebound decreases with increasing duration of viral suppression and, if so, whether rebound rates in patients previously failing antiretroviral regimens ultimately decline to levels as low as those seen in patients who have never experienced virological failure. Methods:All patients from the UK CHIC Study (n = 21 256) who achieved a viral load (VL) of ≤ 50 copies/ml while receiving HAART were followed until viral rebound (two consecutive VL > 400 copies/ml). Patients could re-enter the analysis if they experienced a subsequent VL ≤ 50 copies/ml. Rebound rates were calculated according to the number of regimens previously failed and duration of viral suppression. Results:Of 12 648 patients on HAART 10 237 (80.9%) achieved a VL ≤ 50 copies/ml. During 26 494 person-years (PY) of follow-up, 1853 (18.1%) patients experienced at least one viral rebound ‘event’, with 2460 events in total [rebound rate, 9.3 (range, 8.9–9.7)/100 PY). Within the first year of viral suppression, the rate of viral rebound was 8.3 (7.5–9.1)/100 PY in patients who had not previously failed treatment, increasing to 32.7 (27.6–37.8)/100 PY in patients who had failed more than four regimens. Irrespective of previous treatment failure, rebound rates in those who remained suppressed for > 4 years were similar to those in patients who had at no time experienced treatment failure. Conclusion:After around 4 years of viral suppression rebound rates in individuals with multiple prior treatment failures approach those of individuals with no prior treatment failure.

The epidemiology and clinical correlates of HIV-1 co-receptor tropism in non-subtype B infections from India, Uganda and South Africa

BackgroundThe introduction of C-C chemokine receptor type-5 (CCR5) antagonists as antiretroviral therapy has led to the need to study HIV co-receptor tropism in different HIV-1 subtypes and geographical locations. This study was undertaken to evaluate HIV-1 co-receptor tropism in the developing world where non-B subtypes predominate, in order to assess the therapeutic and prophylactic potential of CCR5 antagonists in these regions.MethodsHIV-1-infected patients were recruited into this prospective, cross-sectional, epidemiologic study from HIV clinics in South Africa, Uganda and India. Patients were infected with subtypes C (South Africa, India) or A or D (Uganda). HIV-1 subtype and co-receptor tropism were determined and analyzed with disease characteristics, including viral load and CD4+ and CD8+ T cell counts.ResultsCCR5-tropic (R5) HIV-1 was detected in 96% of treatment-naïve (TN) and treatment-experienced (TE) patients in India, 71% of TE South African patients, and 86% (subtype A/A1) and 71% (subtype D) of TN and TE Ugandan patients. Dual/mixed-tropic HIV-1 was found in 4% of Indian, 25% of South African and 13% (subtype A/A1) and 29% (subtype D) of Ugandan patients. Prior antiretroviral treatment was associated with decreased R5 tropism; however, this decrease was less in subtype C from India (TE: 94%, TN: 97%) than in subtypes A (TE: 59%; TN: 91%) and D (TE: 30%; TN: 79%). R5 virus infection in all three subtypes correlated with higher CD4+ count.ConclusionsR5 HIV-1 was predominant in TN individuals with HIV-1 subtypes C, A, and D and TE individuals with subtypes C and A. Higher CD4+ count correlated with R5 prevalence, while treatment experience was associated with increased non-R5 infection in all subtypes.

Are previous treatment interruptions associated with higher viral rebound rates in patients with viral suppression

Objective:We investigated whether previous treatment interruptions are associated with a raised risk of viral rebound in individuals who have attained virological suppression. Methods:All patients achieving an undetectable viral load while on therapy were followed until viral rebound or the time of the last viral load. Poisson regression was used to describe the independent impact of treatment interruptions on rebound rates. Results:A total of 12 977 patients from the United Kingdom Collaborative HIV Cohort (UK CHIC) Study achieved a viral load of less than 50 copies/ml. These patients contributed a total of 37 314 person-years of follow-up. The overall rebound rate was 8.07 (7.78, 8.36) per 100 person-years. In adjusted analyses, rates of viral rebound were up to 64% higher (rate ratio 1.64; 1.43, 1.88) in those who had previously interrupted therapy compared with those who had not. Patients who had interrupted at detectable viral loads had up to a 74% (1.74; 1.42, 2.14) higher chance of rebounding compared with those who had not interrupted with a detectable viral load. We found no evidence to suggest interrupting treatment at an undetectable viral load was associated with viral rebound. Conclusion:Among patients with an undetectable viral load, having previously interrupted therapy while the viral load was detectable is associated with a raised risk of rebound.

HIV and AIDS in the People's Republic of China: a collaborative review

The number of individuals diagnosed with HIV in China has risen dramatically in the last two years coincident with increased awareness and an attitude change within government. UNAIDS has suggested that China could have 10 million HIV infected people by 2010. However, antiretroviral treatments and HIV testing are not yet widely available and infected individuals often live in remote areas. It is unlikely that cheaper, locally produced, generic antiretroviral formulations will be available in China in the near future. Consequently, alternative strategies to manage HIV infection are being considered including the use of hydroxyurea, chloroquine and traditional Chinese herbal medicines. It is recognized in China that prevention and educational strategies will need to be at the forefront of approaches to control this epidemic.

The immunological effects of concomitant highly active antiretroviral therapy and liposomal anthracycline treatment of HIV-1-associated Kaposi's sarcoma

A combination of highly active antiretroviral therapy (HAART) and liposomal anthracycline chemotherapy is the standard of care for advanced HIV-associated Kaposis sarcoma, despite concerns that the chemotherapy may adversely affect lymphocyte subsets and HIV viraemia. We showed in 50 patients that liposomal anthracyclines used with HAART did not lead to a significant loss of CD4 or CD8 cells or an increase in HIV-1 viral load during or up to 12 months after chemotherapy.

Five-Year Safety Evaluation of Maraviroc in HIV-1-Infected Treatment-Experienced Patients

Background:Maraviroc is unique among approved antiretroviral drugs in targeting the host-cell chemokine coreceptor type-5 receptor. With its novel mechanism of action, we sought to describe the 5-year safety profile of maraviroc. Methods:Two large phase 3 studies of maraviroc enrolled HIV-infected treatment-experienced patients and followed them up for 5 or more years. Survival and selected clinical end points were identified and assessed. Results:A total of 938 enrolled patients received maraviroc-containing regimens. Rates of death and selected clinical events (eg, hepatic failure, malignancy, and myocardial infarction) were low during follow-up. Conclusions:Maraviroc was generally safe in treatment-experienced participants for >5 years.

Genotypic Analysis of the V3 Region of HIV from Virologic Nonresponders to Maraviroc-Containing Regimens Reveals Distinct Patterns of Failure

ABSTRACT Changes in HIV tropism from R5 to non-R5 or development of drug resistance is often associated with virologic failure in patients treated with maraviroc, a CCR5 antagonist. We sought to examine changes in HIV envelope sequences and inferred tropism in patients who did not respond to maraviroc-based regimens. We selected 181 patients who experienced early virologic failure on maraviroc-containing therapy in the MOTIVATE trials. All patients had R5 HIV by the original Trofile assay before entry. We used population-based sequencing methods and the geno2pheno algorithm to examine changes in tropism and V3 sequences at the time of failure. Using deep sequencing, we assessed whether V3 sequences observed at failure emerged from preexisting subpopulations. From population genotyping data at failure, 90 patients had R5 results, and 91 had non-R5 results. Of the latter group, the geno2pheno false-positive rate (FPR) value fell from a median of 20 at screening to 1.1 at failure. By deep sequencing, the median percentage of non-R5 variants in these patients rose from 1.4% to 99.5% after a median of 4 weeks on maraviroc. In 70% of cases, deep sequencing could detect a pretreatment CXCR4-using subpopulation, which emerged at failure. Overall, there were two distinct patterns of failure of maraviroc. Patients failing with R5 generally had few V3 substitutions and low non-R5 prevalence by deep sequencing. Patients with non-R5 HIV who were failing developed very-high-prevalence non-R5 HIV (median, 99%) and had very low geno2pheno values.