Christopher F. Rowley

Impact of Hepatitis C Virus on Immune Restoration in HIV-Infected Patients Who Start Highly Active Antiretroviral Therapy: A Meta-analysis

BACKGROUND There are conflicting data in the medical literature regarding the degree of immune restoration (as measured by CD4 cell count) in patients who commence highly active antiretroviral therapy (HAART) when coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV), compared with those with HIV infection alone. METHODS We performed a meta-analysis that compared CD4 cell count increases after HAART initiation in HCV-negative and HCV-positive patients who were infected with HIV. Published studies in the English-language medical literature that involved cohorts of HCV-negative and HCV-positive patients who were coinfected with HIV were obtained by searching the Medline, Embase Drugs and Pharmacology, and EBM Review-Cochrane Central Register of Controlled Trials databases. Data were extracted independently from relevant studies by 3 investigators and were used in a fixed-effects meta-analysis to determine the mean difference in the expected CD4 count change in the 2 groups. RESULTS Eight trials involving 6216 patients were analyzed. Patients with HIV-HCV coinfection had a mean increase in the CD4 cell count that was 33.4 cells/mm3 (95% CI, 23.5-43.3 cells/mm3) less than that for HIV-infected patients without HCV infection. The results of the meta-analysis were independent of any one study and were not influenced by the year in which HAART was started. CONCLUSIONS This meta-analysis shows that patients with HIV-HCV coinfection do, in fact, have less immune reconstitution, as determined by CD4 cell count after 48 weeks of HAART, than do patients with HCV infection alone. Future research should examine whether an impaired immunologic response corresponds with meaningful virologic and clinical outcomes.

Reduced Viral Replication Capacity of Human Immunodeficiency Virus Type 1 Subtype C Caused by Cytotoxic-T-Lymphocyte Escape Mutations in HLA-B57 Epitopes of Capsid Protein

ABSTRACT Cytotoxic-T-lymphocyte (CTL) escape mutations in human immunodeficiency viruses encode amino acid substitutions in positions that disrupt CTL targeting, thereby increasing virus survival and conferring a relative fitness benefit. However, it is now clear that CTL escape mutations can also confer a fitness cost, and there is increasing evidence to suggest that in some cases, e.g., escape from HLA-B*57/B*5801-restricted responses, the costs to the escape virus may affect the clinical course of infection. To quantify the magnitude of the costs of HLA-B*57/B*5801 escape, a highly sensitive dual-infection assay that uses synonymous nucleotide sequence tags to quantify viral relative replication capacity (RRC) was developed. We then asked whether such CTL escape mutations had an impact equivalent to that seen for a benchmark mutation, the M184V antiretroviral drug resistance mutation of reverse transcriptase (RRCV184 = 0.86). To answer the question, the RRCs were quantified for escape mutations in three immunodominant HLA-B*57/B*5801 epitopes in capsid: A146P in IW9 (RRCP146 = 0.91), A163G in KF11 (RRCG163 = 0.89), and T242N in TW10 (RRCN242 = 0.86). Individually, the impact of the escape mutations on RRC was comparable to that of M184V, while coexpression of the mutations resulted in substantial further reductions, with the maximum impact observed for the triple mutant (RRCP146-G163-N242 = 0.62). By comparison to M184V, the magnitude of the reductions in RRC caused by the escape mutations, particularly when coexpressed, suggests that the costs of escape are sufficient to affect in vivo viral dynamics and may thus play a role in the protective effect associated with HLA-B*57/B*5801.

Minor resistant variants in nevirapine-exposed infants may predict virologic failure on nevirapine-containing ART.

BACKGROUND Single-dose nevirapine (sdNVP) is widely used to prevent mother-to-child transmission (PMTCT) of HIV-1. This may result in NVP resistance in both mother and infant. The significance of low levels of NVP resistance mutations in infants treated with NVP-containing antiretroviral treatment (ART) is unknown. OBJECTIVES To determine the presence of pre-treatment NVP resistance in HIV-infected infants with and without prior NVP exposure. STUDY DESIGN 33 HIV-1-infected infants in a PMTCT trial received NVP-containing ART (26 infants with prior NVP exposure). Plasma and buffy coat samples obtained prior to ART initiation were evaluated for drug resistance by bulk sequencing and allele-specific PCR (ASPCR). RESULTS ViroSeq identified NVP resistance in 3 of 33 infants; all failed first-line therapy. Pre-ART plasma NVP resistance by ASPCR was detected in 9 of 16 children experiencing virologic failure compared to 4 of 17 children without virologic failure (risk ratio 2.4, CI 0.94-7.8, p=0.08). Proviral resistance was not associated with virologic failure (risk ratio 1.2, CI 0.8-2.0, p=0.40). In the nevirapine-exposed infants, those who started ART before 7 months had higher risk of virologic failure (RR 2.3, CI 0.96-9.2, p=0.11). CONCLUSIONS Low level drug resistance detected in plasma after NVP exposure prior to ART initiation may be associated with virologic failure on ART, while resistance in the DNA reservoir was not predictive of treatment outcome.

Developments in CD4 and Viral Load Monitoring in Resource-Limited Settings

CD4 counts and human immunodeficiency virus (HIV) load testing are essential components of HIV care, and making these tests available in resource-limited settings is critical to the roll-out of HIV treatment globally. Until recently, the evidence supporting the importance of laboratory monitoring in resource-limited settings was lacking, but there is now a consensus emerging that testing should become routine to ensure the longevity of treatment programs. Low-cost, point-of-care testing offers the potential to fill this role as it potentially improves all aspects of HIV care, ranging from the diagnosis and staging of HIV infection in both infants and adults to monitoring for treatment failure once antiretroviral therapy has been initiated. It is imperative for low-cost solutions to become a reality, but it is equally imperative that close scrutiny be given to each new device that hits the market to ensure they perform optimally in all settings.

Suboptimal Addiction Interventions for Patients Hospitalized with Injection Drug Use-Associated Infective Endocarditis

BACKGROUND Infective endocarditis is a serious infection, often resulting from injection drug use. Inpatient treatment regularly focuses on management of infection without attention to the underlying addiction. We aimed to determine the addiction interventions done in patients hospitalized with injection drug use-associated infective endocarditis. METHODS This is a retrospective review of patients hospitalized with injection drug use-associated infective endocarditis from January, 2004 through August, 2014 at a large academic tertiary care center in Boston, Massachusetts. For the initial and subsequent admissions, data were collected regarding addiction interventions, including consultation by social work, addiction clinical nurse and psychiatry, documentation of addiction in the discharge summary plan, plan for medication-assisted treatment and naloxone provision. RESULTS There were 102 patients admitted with injection drug use-associated infective endocarditis, 50 patients (49.0%) were readmitted and 28 (27.5%) patients had ongoing injection drug use at readmission. At initial admission, 86.4% of patients had social work consultation, 23.7% had addiction consultation, and 24.0% had psychiatry consultation. Addiction was mentioned in 55.9% of discharge summary plans, 7.8% of patients had a plan for medication-assisted treatment, and naloxone was never prescribed. Of 102 patients, 26 (25.5%) are deceased. The median age at death was 40.9 years (interquartile range 28.7-48.7). CONCLUSIONS We found that patients hospitalized with injection drug use-associated infective endocarditis had high rates of readmission, recurrent infective endocarditis and death. Despite this, addiction interventions were suboptimal. Improved addiction interventions are imperative in the treatment of injection drug use-associated infective endocarditis.

Sharp increase in rates of HIV transmitted drug resistance at antenatal clinics in Botswana demonstrates the need for routine surveillance

OBJECTIVES The aim of the study was to evaluate for the presence of drug resistance to HIV medications in treatment-naive individuals in Botswana. METHODS Two different populations were evaluated for evidence of HIV drug resistance at three different geographical locations in Botswana. In the first study population, consisting of pregnant females diagnosed with HIV during pregnancy, participants were enrolled at the time of their HIV diagnosis. The second population included pre-ART enrollees at Infectious Diseases Care Clinics (IDCCs) who had a CD4 T cell count >350 cells/μL. RESULTS A total of 422 genotypes were determined: 234 for samples from antenatal clinic (ANC) participants and 188 for samples from IDCC participants. Between 2012 and 2014, 6 of 172 (3.5%) genotypes from ANC participants exhibited transmitted drug resistance (TDR), with 3 (1.7%) showing resistance to first-line ART. In a subset of samples from Gaborone, Botswanas capital and largest city, the TDR rate was 3 in 105 (2.9%), but only 1 in 105 (1.0%) showed first-line ART resistance. Between December 2014 and April 2015, the rate of resistance to any ART in Gaborone was 6 in 62 (9.7%), with 5 (8.1%) exhibiting first-line ART resistance. CONCLUSIONS These data demonstrate that TDR rates for HIV differ geographically and temporally in Botswana, with significant increases in TDR observed at ANCs in Gaborone between 2012 and 2015. These findings stress the importance of continued testing for TDR, particularly as access to HIV treatment increases and guidelines recommend treatment at the time of HIV diagnosis.

Stretching the Scope — Becoming Frontline Addiction-Medicine Providers

Seeing growing numbers of life-threatening infections arising from injection drug use, a group of ID physicians began offering patients with opioid use disorder counseling, naloxone, buprenorphine induction therapy, and essential referrals for long-term treatment.

Abacavir Alters the Transcription of Inflammatory Cytokines in Virologically Suppressed, HIV-Infected Women

Abacavir (ABC) may be associated with a small, increased risk of myocardial infarction in HIV‐infected adults, possibly related to cytokine‐mediated inflammation.

Estimating the prevalence of transmitted HIV drug resistance using pooled samples

In many resource-poor countries, hiv-infected patients receive a standardized antiretroviral cocktail. In these settings, population-level surveillance of drug resistance is needed to characterize the prevalence of resistance mutations and to enable antiretroviral therapy programs to select the optimal regimen for their local population. The surveillance strategy currently recommended by the World Health Organization is prohibitively expensive in some settings and may not provide a sufficiently precise rendering of the emergence of drug resistance. By using a novel assay on pooled sera samples, we decrease surveillance costs while simultaneously increasing the accuracy of drug resistance prevalence estimates for an important mutation that impacts first-line antiretroviral therapy. We present a Bayesian model for pooled-testing data that garners more information from each resistance assay conducted, compared with individual testing. We expand on previous pooling methods to account for uncertainty about the population distribution of within-subject resistance levels. In addition, our model accounts for measurement error of the resistance assay, and this added uncertainty naturally propagates through the Bayesian model to our inference on the prevalence parameter. We conduct a simulation study that informs our pool size recommendations and that shows that this model renders the prevalence parameter identifiable in instances when an existing non-model-based estimator fails.

Reimagining Long-term Antibiotics in Persons Who Inject Drugs: Time to Shift the Status Quo?

Medical Service, Veterans Affairs Medical Center, Washington, DC; George Washington University School of Medicine and Health Sciences, Washington, DC; Uniformed Services University of the Health Sciences, Bethesda, Maryland; DC Partnership for HIV/AIDS Progress, Washington, DC; Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Harvard T.H. Chan School of Public Health, Boston, Massachusetts.