Edward R. Cachay

Update on hepatitis C virus resistance to direct-acting antiviral agents

Resistance to direct-acting antiviral (DAA) agents against hepatitis C virus (HCV) infection is driven by the selection of mutations at different positions in the NS3 protease, NS5B polymerase and NS5A proteins. With the exception of NS5B nucleos(t)ide inhibitors, most DAAs possess a low genetic barrier to resistance, with significant cross-resistance between compounds belonging to the same family. However, a specific mutation profile is associated with each agent or drug class and varies depending on the genotype/subtype (e.g., genotype 1b showed higher rates of sustained virological response (SVR) and a higher genetic barrier for resistance than genotype 1a). Moreover, some resistance mutations exist as natural polymorphisms in certain genotypes/subtypes at frequencies that require baseline drug resistance testing before recommending certain antivirals. For example, the polymorphism Q80K is frequently found among genotype 1a (19-48%) and is associated with resistance to simeprevir. Similarly, L31M and Y93H, key resistance mutations to NS5A inhibitors, are frequently found (6-12%) among NS5A genotype 1 sequences. In particular, the presence of these polymorphisms may be of relevance in poorly interferon-responsive patients (i.e., null responders and non-CC IL28B) under DAA-based therapies in combination with pegylated interferon-α plus ribavirin. The relevance of pre-existing resistance mutations for responses to interferon-free DAA therapies is unclear for most regimens and requires further study.

Herpes simplex virus 2 serostatus and viral loads of HIV-1 in blood and semen as risk factors for HIV transmission among men who have sex with men.

Objective:Human immunodeficiency virus type 1 blood plasma viral load is correlated with the sexual transmission of HIV, although transmission from men involves virus from semen instead of blood. We quantified HIV-1 RNA in the blood and semen of men who did or did not transmit HIV to their sex partners. We compared the relationships of HIV-1 transmission risk with blood plasma viral load, seminal plasma viral load, herpes simplex virus 2 serostatus and other factors. Design:A case–control study. Methods:Participants were men evaluated for primary HIV infection and their recent male sex partners. They were interviewed, and clinical specimens were collected. Epidemiologic and phylogenetic linkages were determined by history and molecular techniques. Couples were grouped on the basis of transmission after exposure. Fishers exact test and Wilcoxon tests were used for comparisons between groups. Multivariable logistic regressions were fit to identify independent predictors of transmission. Results:HIV-transmitting partners (n = 15) had a higher median seminal plasma viral load (P < 0.015) and median blood plasma viral load (P < 0.001) than nontransmitting partners (n = 32). Herpes simplex virus 2 serostatus was associated with transmission only when the HIV-infected source partner was herpes simplex virus 2 seropositive and the HIV-exposed partner was not (odds ratio 16, P < 0.03). Adjusting for other factors, HIV transmission was significantly associated with blood plasma viral load (odds ratio 13.4, P < 0.02) but not seminal plasma viral load (odds ratio 0.69, P = not significant). Conclusion:Blood and seminal plasma viral load were both associated with human immunodeficiency virus type 1 transmission, but blood plasma viral load was the stronger predictor in this cohort. Herpes simplex virus 2 coinfection was associated with the risk of transmission but not acquisition of human immunodeficiency virus type 1.

Clinical Utility of HIV Standard Genotyping among Antiretroviral-Naive Individuals with Unknown Duration of Infection

In clinical settings, we have found a high rate of human immunodeficiency virus (HIV) drug resistance among antiretroviral-naive patients for whom the duration of infection was unknown. These high rates were most likely the result of both transmitted resistance and informal antiretroviral use, and they suggest that routine resistance testing among antiretroviral-naive patients would be a cost-effective clinical practice.

Treatment of HIV-related inflammatory cerebral cryptococcoma with adalimumab.

Cryptococcomas have been described in AIDS patients in the setting of immune reconstitution inflammatory syndrome. We report the first case of human immunodeficiency virus-related inflammatory cerebral cryptococcoma to be treated with a recombinant human monoclonal tumor necrosis factor antagonist.

Screening for Potentially Transmitting Sexual Risk Behaviors, Urethral Sexually Transmitted Infection, and Sildenafil Use Among Males Entering Care for HIV Infection

The study aims were to evaluate the prevalence and predictors of sexual risk behaviors and urethral sexually transmitted disease (STD) among males entering care for HIV infection and to examine if sildenafil prescriptions are associated with potentially transmitting sexual risk behavior (PTSRB). The research design included (1) self-administered questionnaire of symptoms of sexually transmitted infection (STI), number of recent sex partners, unprotected sexual risk behaviors, use of drugs/alcohol during sex, and HIV disclosure; (2) urine gonorrhea/chlamydia polymerase chain reaction (PCR); and (3) record review for sildenafil prescriptions. A PTSRB was defined as insertive anal, vaginal, or oral sex without a condom. Between March 2001 and March 2002, 413 entrants were surveyed. The prevalence of positive urine PCR among those with and without urethral symptoms was 16.7% and 2.4%, respectively. Fifty-one percent met criteria for PTSRB during the preceding month. Those reporting PTSRB were more likely to report multiple partners. In a multiple logistic regression model, the following were significant (p < 0.05) predictors of PTSRB: drug or alcohol use during sex; white race; only male partners, and sildenafil use. Drug use during sex was associated both with more sex partners and more sexual risk behaviors. Always disclosing HIV status was associated with fewer partners. There was a high prevalence of PTSRB among HIV-infected males entering care. Men who have sex with men (MSM), white race, drug/alcohol use during sex, and sildenafil use were independent risk factors. PTSRB was associated with having multiple partners. Physicians should discuss risk behaviors before prescribing sildenafil.

Estimating the accuracy of anal cytology in the presence of an imperfect reference standard.

Background The study aim is to estimate sensitivity and specificity of anal cytology for histologic HSIL in analyses adjusted for the imperfect biopsy reference standard. Methods and Principal Findings Retrospective cohort study of an anal dysplasia screening program for HIV infected adults. We estimated the prevalence of histologic HSIL by concurrent cytology category and the associated cytology ROC area. Cytology operating characteristics for HSIL were estimated and adjusted for the imperfect reference standard by 3 methodologies. The study cohort included 261 patients with 3 available measures: (1) referral cytology; (2) HRA cytology; and (3) HRA directed biopsy. The prevalence of biopsy HSIL varied according to the concurrent HRA cytology result: 64.5% for HSIL or ASC-H, 12.6% for LSIL, 10.9% for ASCUS, and 6.3% for no abnormality. The cytology ROC area was 0.78. The observed prevalence of HSIL was 37% (referral cytology), 24% (HRA cytology), and 24% (HRA biopsy). Unadjusted estimates of sensitivity and specificity of cytology were 0.66 and 0.90, respectively. Adjusted estimates varied from 0.47–0.89 (sensitivity) and 0.89—1.0 (specificity). Conclusions Analysis of a single dataset yields widely different estimates of anal cytology operating characteristics that depend on difficult to verify assumptions regarding the accuracy of the imperfect reference standard.

Clinical, biochemical and histological differences between HIV-associated NAFLD and primary NAFLD: a case–control study

There are limited data regarding the clinical, biochemical and liver histological characteristics of patients with HIV‐associated nonalcoholic fatty liver disease (NAFLD), and whether this entity differs in presentation and severity from primary NAFLD

The Hepatitis C Cascade of Care among HIV Infected Patients: A Call to Address Ongoing Barriers to Care

Background The aims were to investigate the hepatitis C (HCV) cascade of care among HIV-infected patients and to identify reasons for not referring for and not initiating HCV therapy after completion of HCV treatment staging. Design and Methods Retrospective cohort analysis of HIV-infected patients under care at the University of California, San Diego (UCSD). We identified patients screened for and diagnosed with active HCV infection. Logistic regression analyses were used to identify factors associated with lack of referral for HCV therapy. Electronic medical records were reviewed to ascertain reasons for not initiating HCV therapy. Results Between 2008 and 2012, 4725 HIV-infected patients received care at the UCSD Owen clinic. Most patients [4534 (96%)] were screened for HCV, 748 (16%) patients had reactive serum HCV antibodies but only 542 patients had active HCV infection. Lack of engagement in care was the most important predictor of non-referral for HCV therapy [odds ratio (OR): 5.08, 95% confidence interval 3.24–6.97, p<0.00001]. Other significant predictors included unstable housing (OR: 2.26), AIDS (OR: 1.83), having a detectable HIV viral load (OR: 1.98) and being non-white (OR: 1.67). The most common reason (40%) for not initiating or deferring HCV therapy was the presence of ongoing barriers to care. Conclusions Screening for HCV in HIV-infected patients linked to care is high but almost half of patients diagnosed with HCV are not referred for HCV therapy. Despite improvements in HCV therapy the benefits will not be realized unless effective measures for dealing with barriers to care are implemented.

Early Impact and Performance Characteristics of an Established Anal Dysplasia Screening Program: Program Evaluation Considerations

Background: Screening for invasive anal cancer and its precursors is being increasingly advocated as a response to increasing incidence among HIV-infected persons. We implemented a comprehensive screening program in 2001 and report our early experience to inform monitoring and evaluation of such programs. Our research aims were: (1) to estimate incidence of and mortality from invasive anal cancer (IAC) before (1995-2000) and after (2001-2005) screening program implementation and (2) to examine potential screening program quality indicators. Methods: The study cohort included all patients under care for HIV infection at UCSD Owen Clinic between 1995-2005. Person-time incidence rates (IR) and case survival of IAC were estimated for the pre-screening (1995-2000) and post-screening (2001-2005) periods. High resolution anoscopy (HRA) operator accuracy was estimated by kappa agreement between cyto-histologic comparisons. Program quality indicators included: (1) screening coverage; (2) percent technically unsatisfactory cytology smears; (3) time between 1st abnormal cytology and 1st HRA; and (4) time between last clinic visit and last cytology. Results: 28 cases of IAC and 13,411 person-years were observed between 1995-2005. IRs (95% CI) pre-screening and post-screening were 199 and 216 per 100,000 person-years, respectively. There was no routine treatment of high grade squamous intraepithelial lesions (HSIL) during the study period. The percent of patients with IAC requiring chemoradiation decreased from 90.9% to 70.6% (p=0.36). There was a significant improvement in cyto-histologic agreement at HRA with increasing operator experience (r=0.92, p=0.025). Screening coverage was 73% of the target population. Among 14 providers, the percent unsatisfactory cytology smears averaged 27% but varied from 0 – 62%. The median time from 1st abnormal cytology to 1st HRA was 258 days. The median interval between the last cytology and the last clinic visit was 207 days. Conclusion: (1) The overall IR of IAC did not decline in the screening era and was higher than previous estimates for HIV cohorts; (2) stage shift to IAC of more favorable prognosis is a reasonable screening goal; (3) HRA accuracy varied by provider experience; (4) because of delay in access to HRA, digital rectal exam should be combined with cytology screening to detect palpable disease.

Herpes Simplex Virus Type 2 Infection Does Not Influence Viral Dynamics during Early HIV-1 Infection

OBJECTIVE We sought to compare baseline and longitudinal plasma HIV-1 loads between herpes simplex virus type 2 (HSV-2)-seropositive and -seronegative individuals who are enrolled in a primary HIV-1 infection cohort in San Diego, California. DESIGN The study was a retrospective cohort analysis. METHODS We categorized antiretroviral-naive subjects on the basis of HSV-2 serostatus at baseline using an HSV-2 enzyme immunoassay. Low positive results (1.1-3.5) were confirmed by Western blotting. We compared baseline HIV-1 loads of the 2 groups using a linear model. To detect differences in HIV-1 dynamics, we analyzed longitudinal viral loads using a flexible semiparametric model, controlling for the time to antiretroviral therapy and stratifying by HIV-1 infection stage at entry. RESULTS We studied 294 adult men. Ninety percent reported sex with men as their main HIV-1 risk factor. The seroprevalence of HSV-2 was 41.5%. The HSV-2-seropositive and -seronegative groups had similar baseline HIV-1 loads during acute infection (5.52 vs. 5.72 log(10) copies/mL; P=.39) and early infection (4.57 vs. 4.67 log(10) copies/mL; P=.5). Longitudinally, the difference in HIV-1 loads between HSV-2-seropositive and -seronegative men remained close to 0 during the first year of infection. CONCLUSIONS HSV-2 serostatus has minimal influence on the dynamics of HIV-1 during acute and early HIV-1 infection.