Gail V. Matthews

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).

Acute hepatitis C in HIV-infected men who have sex with men: an emerging sexually transmitted infection.

Since 2000 outbreaks of acute hepatitis C virus (HCV) among HIV-positive men who have sex with men (MSM) who denied injecting drug use have been reported from Europe, the United States, Canada and Australia. Given the burden of liver disease, in particular HCV, on the morbidity and mortality in HIV patients in the era of combination antiretroviral therapy, the rapid and significant rise in the incidence of HCV in the HIV-infected MSM population in high-income countries is alarming. This relates to a significant change in the epidemiology of HCV that has occurred, with HCV emerging as a sexually transmitted infection within this population. Work to date suggests that this permucosal HCV transmission results from high-risk sexual and noninjecting drug use behaviours, reopening the discussion on the importance of sexual transmission. Given this occurs almost exclusively in HIV-infected MSM, HIV probably has a critical role mediated either through behavioural and/or biological factors. Finally, the management of acute HCV in HIV infection is complicated by concomitant HIV infection and combination antiretroviral therapy. This review will synthesize the most recent epidemiological, immunological and management issues that have emerged as a result of the epidemic of acute HCV among HIV-infected MSM.

IL28B, HLA-C, and KIR variants additively predict response to therapy in chronic hepatitis C virus infection in a European Cohort: a cross-sectional study.

Vijayaprakash Suppiah and colleagues show that genotyping hepatitis C patients for the IL28B, HLA-C, and KIR genes improves the ability to predict whether or not patients will respond to antiviral treatment.

Potential Role for Interleukin-28B Genotype in Treatment Decision-Making in Recent Hepatitis C Virus Infection

Polymorphisms in the IL28B (interleukin‐28B) gene region are important in predicting outcome following therapy for chronic hepatitis C virus (HCV) infection. We evaluated the role of IL28B in spontaneous and treatment‐induced clearance following recent HCV infection. The Australian Trial in Acute Hepatitis C (ATAHC) was a study of the natural history and treatment of recent HCV, as defined by positive anti‐HCV antibody, preceded by either acute clinical HCV infection within the prior 12 months or seroconversion within the prior 24 months. Factors associated with spontaneous and treatment‐induced HCV clearance, including variations in IL28B, were assessed. Among 163 participants, 132 were untreated (n = 52) or had persistent infection (infection duration ≥26 weeks) at treatment initiation (n = 80). Spontaneous clearance was observed in 23% (30 of 132 participants). In Cox proportional hazards analysis (without IL28B), HCV seroconversion illness with jaundice was the only factor predicting spontaneous clearance (adjusted hazards ratio = 2.86; 95% confidence interval = 1.24, 6.59; P = 0.014). Among participants with IL28B genotyping (n = 102 of 163 overall and 79 of 132 for the spontaneous clearance population), rs8099917 TT homozygosity (versus GT/GG) was the only factor independently predicting time to spontaneous clearance (adjusted hazard ratio = 3.78; 95% confidence interval = 1.04, 13.76; P = 0.044). Participants with seroconversion illness with jaundice were more frequently rs8099917 TT homozygotes than other (GG/GT) genotypes (32% versus 5%, P = 0.047). Among participants adherent to treatment and who had IL28B genotyping (n = 54), sustained virologic response was similar among TT homozygotes (18 of 29 participants, 62%) and those with GG/GT genotype (16 of 25, 64%, P = 0.884). Conclusion: During recent HCV infection, genetic variations in IL28B region were associated with spontaneous but not treatment‐induced clearance. Early therapeutic intervention could be recommended for individuals with unfavorable IL28B genotypes. (HEPATOLOGY 2010;)

Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial

BACKGROUND Hepatitis C virus (HCV) infection is a leading cause of morbidity and mortality in patients with HIV-1. The C-EDGE CO-INFECTION study assessed the efficacy, safety, and tolerability of grazoprevir (MK-5172) plus elbasvir (MK-8742) in patients with HCV and HIV co-infection. METHODS In this uncontrolled, non-randomised, phase 3, open-label, single-arm study, treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection and HIV co-infection, with or without cirrhosis, were enrolled from 37 centres in nine countries across Europe, the USA, and Australia. Patients were either naive to treatment with any antiretroviral therapy (ART) or stable on ART for at least 8 weeks. All patients received grazoprevir 100 mg plus elbasvir 50 mg in a fixed-dose combination tablet once daily for 12 weeks. The primary endpoint was sustained virological response (HCV RNA <15 IU/mL) 12 weeks after the end of therapy (SVR12). The primary population for efficacy analyses was all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT02105662. FINDINGS Between June 11, 2014, and Aug 29, 2014, 218 patients were enrolled and received grazoprevir plus elbasvir for 12 weeks, all of whom completed follow-up at week 12. SVR12 was achieved by 210 (96%) of 218 patients (95% CI 92·9-98·4). One patient did not achieve SVR12 because of a non-virological reason, and seven patients without cirrhosis relapsed (two subsequently confirmed as reinfections). All 35 patients with cirrhosis achieved SVR12. The most common adverse events were fatigue (29; 13%), headache (27; 12%), and nausea (20; 9%). No patient discontinued treatment because of an adverse event. Two patients receiving ART had transient HIV viraemia. INTERPRETATION This HCV treatment regimen seems to be effective and well tolerated for patients co-infected with HIV with or without cirrhosis. These data are consistent with previous trials of this regimen in the monoinfected population. This regimen continues to be studied in phase 3 trials. FUNDING Merck Sharp & Dohme Corp.

Characteristics of drug resistant HBV in an international collaborative study of HIV-HBV-infected individuals on extended lamivudine therapy.

Background:Little is known about the prevalence and pattern of hepatitis B virus (HBV) mutations in HIV/HBV co-infected individuals on long-term lamivudine (3TC) therapy. Methods:HBV polymerase/envelope/basal core promoter/pre-core sequences from 81 HIV–HBV co-infected persons who received at least 6 months 3TC were compared to HBV reference sequences. Host and viral characteristics associated with HBV mutations were determined. Results:HBV viraemia was detected in 53 persons (65%) and was associated with lower CD4 cell count nadir and higher HIV RNA at the time of testing but not with 3TC duration. Known 3TC-resistant mutations occurred in 50% and 94% of viremic patients with < 2 years and > 4 years 3TC, respectively. The CD4 cell count at testing was significantly higher in those with 3TC-resistant mutations. The triple polymerase mutant (rtL173V, rtL180M, rtM204V), which behaves as a vaccine escape mutant in vitro, occurred in 17% of viraemic patients. Polymerase mutations that may confer resistance to other anti-HBV agents were also detected. Conclusions:In HIV–HBV co-infected patients, greater immunocompromise is associated with continued HBV viraemia while on 3TC, and development of 3TC-resistant mutations are inevitable with prolonged 3TC use. These mutant viruses may limit future therapeutic options due to cross-resistance or may produce HBV vaccine escape mutants. Thus, timing and selection of antiretroviral therapy is critical in this population.

Effective Treatment of Injecting Drug Users With Recently Acquired Hepatitis C Virus Infection

BACKGROUND & AIMS Patients with acute hepatitis C virus (HCV) infection who receive treatment achieve high rates of sustained virologic response (SVR), but few studies have examined outcomes among injecting drug users (IDUs). We evaluated the efficacy of treatment of recent HCV infection in IDUs with acute and early chronic HCV. METHODS We analyzed data from the Australian Trial in Acute Hepatitis C-a prospective study of the natural history and treatment outcomes of patients with recent HCV infection. Participants eligible for the study had their first anti-HCV antibody-positive test result within the past 6 months and either acute clinical HCV within the past 12 months or documented anti-HCV seroconversion within 24 months. Participants with HCV received pegylated interferon-alfa-2a (180 microg/wk, n = 74); those with HCV/human immunodeficiency virus (HIV) co-infection received pegylated interferon-alfa-2a (180 microg/wk) with ribavirin (n = 35) for 24 weeks. RESULTS From June 2004 to February 2008, 167 participants were enrolled in the Australian Trial in Acute Hepatitis C; 79% had injected drugs in the previous 6 months. Among 74 with only HCV, the SVRs were 55% and 72% by intention-to-treat and per-protocol analysis, respectively. In multivariate analyses, baseline factors independently associated with lower SVR included decreased social functioning and current opiate pharmacotherapy. Adherent participants had higher SVR rates (63% vs 29%; P = .025). Of the 35 participants with HCV/HIV co-infection, the SVRs were 74% and 75% by intention-to-treat and per-protocol analysis, respectively. CONCLUSIONS Treatment of recent HCV infection among IDUs, including those with HIV co-infection, is effective. Strategies to engage socially marginalized individuals and increase adherence should improve treatment outcomes in this population.

Virological suppression at 6 months is related to choice of initial regimen in antiretroviral-naive patients: a cohort study

Background Guidelines recommend both protease inhibitor (PI)- and non-nucleoside reverse transcriptase inhibitor (NNRTI)-containing regimens for initial therapy in HIV-positive individuals whilst clinical trial data comparing treatment options remain limited. Objective To assess whether drug selection (PI versus NNRTI) in antiretroviral-naive patients is related to virological response at 6 months within a clinical cohort. Design Databases from two large clinics were used to identify all treatment-naive patients initiating highly active antiretroviral therapy (PI/ two PI or NNRTI). Statistical models determined the likelihood of suppressing HIV viral load < 500 copies/ml, the risk of treatment failure by 6 months, and factors associated with treatment success. Results Of 1109 potentially eligible patients 888 met study criteria and were included; 484 were prescribed a PI (40% indinavir, 41% nelfinavir) and 404 were prescribed NNRTI (40% efavirenz, 60% nevirapine). Three treatment arms were compared: efavirenz versus nevirapine versus PI. After stratification by year and centre and adjustment for baseline variables, only treatment group and baseline viral load remained significantly associated with virological suppression at 6 months. Patients on efavirenz were significantly more likely to achieve an undetectable viral load than those on PI or nevirapine. The relative hazard for nevirapine was 0.77 (95% confidence interval, 0.61–0.96, P = 0.02) and that for PI was 0.74 (95% confidence interval, 0.58–0.94, P = 0.01). Efavirenz also performed better in the analysis of treatment failure at 6 months. Conclusion Although observational cohort data may be susceptible to significant bias, this study suggests a better initial virological response for efavirenz compared to either nevirapine or the PI. Clinical trial data is required to confirm these findings.

A randomized trial of combination hepatitis B therapy in HIV/HBV coinfected antiretroviral naïve individuals in Thailand

Coinfection with human immunodeficiency virus (HIV) and hepatitis B virus (HBV) is associated with considerable liver disease morbidity and mortality. Emerging HIV epidemics in areas of high HBV endemicity such as Asia are expanding the population with HIV/HBV coinfection. Limited randomized trial data exist to support current guidelines for HBV combination therapy in HIV/HBV coinfection. The objective of this prospective randomized clinical trial was to compare the strategy of HBV monotherapy with lamivudine (LAM) or tenofovir disoproxil fumarate (TDF) versus HBV combination therapy with LAM/TDF in antiretroviral‐naïve HIV/HBV‐coinfected subjects in Thailand. Thirty‐six HIV/HBV‐coinfected subjects initiating highly active antiretroviral therapy (HAART) were randomized to either LAM (arm 1), TDF (arm 2), or LAM/TDF (arm 3) as HBV‐active drugs within HAART. At week 48, time‐weighted area under the curve analysis revealed that the median HBV DNA reduction from baseline was 4.07 log10 c/mL in arm 1, 4.57 log10 c/mL in arm 2, and 4.73 log10 c/mL in arm 3 (P = 0.70). HBV DNA suppressed to <3 log10 c/mL in 46% in arm 1, 92% in arm 2, and 91% in arm 3 (P = 0.013, intent‐to‐treat analysis). HBV‐resistant changes were detected in two subjects, both in arm 1. Hepatitis B e antigen (HBeAg) loss was observed in 33% of HBeAg‐positive subjects, and 8% experienced hepatitis B surface antigen loss. Hepatic flare was observed in 25% of subjects. Conclusion: LAM monotherapy resulted in a greater proportion of subjects with HBV DNA >3 log10 c/mL at week 48 and in early resistance development. This study confirms current treatment guidelines that recommend a TDF‐based regimen as the treatment of choice for HIV/HBV coinfection, but does not demonstrate any advantage of HBV combination therapy in this short‐term setting. (HEPATOLOGY 2008.)

Characteristics and Treatment Outcomes among HIV-Infected Individuals in the Australian Trial in Acute Hepatitis C

BACKGROUND The Australian Trial in Acute Hepatitis C (ATAHC) is a National Institutes of Health-funded prospective cohort study of the natural history and efficacy of treatment in individuals with recently acquired hepatitis C. Enrollment is open to both human immunodeficiency virus (HIV)-infected and -uninfected individuals. The aim of this article was to evaluate characteristics and virological outcomes among HIV-infected individuals enrolled in ATAHC. METHODS Eligibility criteria included the first positive result of testing for anti-hepatitis C virus (HCV) antibody within 6 months and either clinical hepatitis diagnosed within the past 12 months or documented anti-HCV seroconversion within the past 24 months. RESULTS Of the initial 103 patients enrolled, 27 (26%) were HIV infected. HIV-infected patients were more likely to be older, to have HCV genotype 1 infection and high levels of HCV RNA at baseline than were HCV-monoinfected patients. Sexual acquisition accounted for the majority (56%) of HCV infections among HIV-infected patients, compared with only 8% of HCV-monoinfected patients. The median duration from estimated HCV infection to treatment was 30 weeks. Treatment with 24 weeks of pegylated interferon and ribavirin resulted in rates of undetectability of HCV RNA of 95%, 90%, and 80% at weeks 12, 24, and 48, respectively. Undetectability at week 4 was achieved in 44% of patients and yielded positive and negative predictive values for sustained virological response of 100% and 33%, respectively. CONCLUSIONS Significant differences were demonstrated between HIV-infected and HIV-uninfected individuals enrolled in ATAHC. Treatment responses among HIV-infected individuals with both acute and early chronic infection are encouraging and support regular HCV screening of high-risk individuals and early treatment for recently acquired HCV infection.