Mamta K. Jain

Changes in mortality related to human immunodeficiency virus infection: comparative analysis of inpatient deaths in 1995 and in 1999-2000.

We conducted a retrospective chart review of human immunodeficiency virus (HIV)-infected patients who died in 1995 and in 1999-2000. We found an increase in the proportion of patients who died from an illness that was not related to acquired immunodeficiency syndrome (AIDS). Although there was a decrease in the prevalence of AIDS-defining illnesses, >85% of patients died with CD4 counts of <200 cells/microL. The leading cause of death was Pneumocystis carinii pneumonia (PCP). Nonadherence to therapy and new diagnosis of HIV infection were the leading reasons why patients were not receiving antiretroviral therapy. The leading causes of non-AIDS-related deaths in 1999-2000 were non-AIDS-defining infections and end-stage liver disease. At our hospital, PCP remains an important cause of death in the highly active antiretroviral therapy (HAART) era, possibly because >50% of HIV-infected patients who died were not receiving HAART. AIDS-defining illnesses continue to be a major cause of mortality in the HAART era in populations where access to care and adherence to HAART is limited.

Treatment of hepatitis B with lamivudine and tenofovir in HIV/HBV-coinfected patients: Factors associated with response

Summary.  As therapy for human immunodeficiency virus (HIV) infection evolves, optimizing hepatitis B virus (HBV) treatment and identifying factors that impact its response in the HIV/HBV‐coinfected population is critical. We identified retrospectively 45 HBV/HIV‐coinfected patients with detectable HBV DNA by the Bayer VERSANT® HBV 3.0 bDNA assay (limit of quantification 2000 copies/mL) at baseline and/or year 1 of therapy. Patients were divided into three groups based on the active HBV agent in their antiretroviral regimen: group 1 (n = 15) received lamivudine; group 2 (n = 10), lamivudine plus tenofovir and group 3 (n = 20), lamivudine followed by lamivudine plus tenofovir. HBV genotypes and resistance profiles were determined by the Bayer Trugene® HBV 1.0 assay. More patients in group 2 achieved HBV DNA suppression below 2000 copies/mL (80%), loss of HBe antigen (HBeAg) (40%) and loss of HBeAg and gain of anti‐HBe (20%) than did patients in group 1 or 3. More patients with HBV genotype A, achieved HBV DNA suppression <2000 copies/mL than did patients with non‐A genotypes [74% (26/35) vs 20% (2/10)], respectively (P = 0.003). Risk for virological nonresponse was significant in those with non‐A genotypes [odds ratio (OR) 11.1; 95% CI: 2.0–50], previous HIV therapy (OR 6.5; 95% CI: 1.2–35) and <90% compliance (OR 3.7; 95% CI: 0.99–14.3). Simultaneous therapy with lamivudine/tenofovir suppresses HBV DNA more effectively than lamivudine or tenofovir added to lamivudine. More patients infected with HBV genotype A responded than the non‐A patients, regardless of therapeutic regimen, compliance or prior HIV therapy.

The RADAR study: week 48 safety and efficacy of RAltegravir combined with boosted DARunavir compared to tenofovir/emtricitabine combined with boosted darunavir in antiretroviral-naive patients. Impact on bone health.

Background NRTI-sparing regimens may avoid long-term mitochondrial, bone and renal toxicities and maintain viral suppression. Methods In the RADAR study, 85 antiretroviral-naïve HIV-infected patients were randomized to receive either raltegravir (RAL) (n = 42) or tenofovir/emtricitabine (TDF/FTC) (n = 43), each with ritonavir-boosted darunavir (DRV/r). Virologic efficacy was assessed at weeks 24 and 48. Bone mineral density (BMD) was assessed by dual energy X-ray absorptiometry (DXA) scan at baseline and week 48, and bone turnover markers (BTM) assessed at weeks 0, 16 and 48. Results Using an intention-to-treat analysis, 62.5% of RAL subjects and 83.7% of TDF/FTC subjects were responders (VL<48 copies/mL) at week 48 (p = 0.045; chi-square test). The proportions of patients achieving VL<200 copies/mL were similar: 72.5% and 86.0% (p = 0.175). Premature treatment discontinuation was the main cause for failure. No treatment-emergent resistance was observed. Changes from baseline in RAL vs. TDF/FTC for CD4+ (+199 vs. +216 cells/µL, p = 0.63), total cholesterol/HDL (−0.25 vs. −0.71 mg/dL (p = 0.270), and eGFR (−4.4 vs. −7.9 ml/min, p = 0.44) were comparable between groups. Changes in subtotal BMD to week 48 were: +9.2 with RAL vs. −7 g/cm2 with TDF/FTC (p = 0.002). Mean CTX changes were +0.04 vs. +0.24 ng/mL (p = 0.001), and mean P1NP changes were +3.59 vs. +30.09 ng/mL (p = 0.023). BTM changes at week 16 predicted change in BMD by week 48 (R = −0.394, p = 0.003 for CTX; and R = −0.477, p<0.001 for P1NP). Conclusion The NRTI-sparing regimen RAL+DRV/r did not achieve similar week 48 virologic efficacy compared with TDF/FTC+DRV/r, but was better with regard to markers of bone health. Trial Registration ClinicalTrials.gov NCT 00677300

Gamma/Delta T-Cell Functional Responses Differ after Pathogenic Human Immunodeficiency Virus and Nonpathogenic Simian Immunodeficiency Virus Infections

ABSTRACT The objective of this study was to functionally assess gamma/delta (γδ) T cells following pathogenic human immunodeficiency virus (HIV) infection of humans and nonpathogenic simian immunodeficiency virus (SIV) infection of sooty mangabeys. γδ T cells were obtained from peripheral blood samples from patients and sooty mangabeys that exhibited either a CD4-healthy (>200 CD4+ T cells/μl blood) or CD4-low (<200 CD4 cells/μl blood) phenotype. Cytokine flow cytometry was utilized to assess production of Th1 cytokines tumor necrosis factor alpha and gamma interferon following ex vivo stimulation with either phorbol myristate acetate/ionomycin or the Vδ2 γδ T-cell receptor agonist isopentenyl pyrophosphate. Sooty mangabeys were observed to have higher percentages of γδ T cells in their peripheral blood than humans did. Following stimulation, γδ T cells from SIV-positive (SIV+) mangabeys maintained or increased their ability to express the Th1 cytokines regardless of CD4+ T-cell levels. In contrast, HIV-positive (HIV+) patients exhibited a decreased percentage of γδ T cells expressing Th1 cytokines following stimulation. This dysfunction is primarily within the Vδ2+ γδ T-cell subset which incurred both a decreased overall level in the blood and a reduced Th1 cytokine production. Patients treated with highly active antiretroviral therapy exhibited a partial restoration in their γδ T-cell Th1 cytokine response that was intermediate between the responses of the uninfected and HIV+ patients. The SIV+ sooty mangabey natural hosts, which do not proceed to clinical AIDS, provide evidence that γδ T-cell dysfunction occurs in HIV+ patients and may contribute to HIV disease progression.

Effect of Patient navigation with or without financial incentives on viral suppression among hospitalized patients with HIV infection and substance use a randomized clinical trial

IMPORTANCE Substance use is a major driver of the HIV epidemic and is associated with poor HIV care outcomes. Patient navigation (care coordination with case management) and the use of financial incentives for achieving predetermined outcomes are interventions increasingly promoted to engage patients in substance use disorders treatment and HIV care, but there is little evidence for their efficacy in improving HIV-1 viral suppression rates. OBJECTIVE To assess the effect of a structured patient navigation intervention with or without financial incentives to improve HIV-1 viral suppression rates among patients with elevated HIV-1 viral loads and substance use recruited as hospital inpatients. DESIGN, SETTING, AND PARTICIPANTS From July 2012 through January 2014, 801 patients with HIV infection and substance use from 11 hospitals across the United States were randomly assigned to receive patient navigation alone (n = 266), patient navigation plus financial incentives (n = 271), or treatment as usual (n = 264). HIV-1 plasma viral load was measured at baseline and at 6 and 12 months. INTERVENTIONS Patient navigation included up to 11 sessions of care coordination with case management and motivational interviewing techniques over 6 months. Financial incentives (up to

Suppression of HBV by Tenofovir in HBV/HIV Coinfected Patients: A Systematic Review and Meta-Analysis

1160) were provided for achieving targeted behaviors aimed at reducing substance use, increasing engagement in HIV care, and improving HIV outcomes. Treatment as usual was the standard practice at each hospital for linking hospitalized patients to outpatient HIV care and substance use disorders treatment. MAIN OUTCOMES AND MEASURES The primary outcome was HIV viral suppression (≤200 copies/mL) relative to viral nonsuppression or death at the 12-month follow-up. RESULTS Of 801 patients randomized, 261 (32.6%) were women (mean [SD] age, 44.6 years [10.0 years]). There were no differences in rates of HIV viral suppression versus nonsuppression or death among the 3 groups at 12 months. Eighty-five of 249 patients (34.1%) in the usual-treatment group experienced treatment success compared with 89 of 249 patients (35.7%) in the navigation-only group for a treatment difference of 1.6% (95% CI, -6.8% to 10.0%; P = .80) and compared with 98 of 254 patients (38.6%) in the navigation-plus-incentives group for a treatment difference of 4.5% (95% CI -4.0% to 12.8%; P = .68). The treatment difference between the navigation-only and the navigation-plus-incentives group was -2.8% (95% CI, -11.3% to 5.6%; P = .68). CONCLUSIONS AND RELEVANCE Among hospitalized patients with HIV infection and substance use, patient navigation with or without financial incentives did not have a beneficial effect on HIV viral suppression relative to nonsuppression or death at 12 months vs treatment as usual. These findings do not support these interventions in this setting. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01612169.

Hepatitis C is associated with type 2 diabetes mellitus in HIV-infected persons without traditional risk factors

Background Hepatitis B coinfection is common in HIV-positive individuals and as antiretroviral therapy has made death due to AIDS less common, hepatitis has become increasingly important. Several drugs are available to treat hepatitis B. The most potent and the one with the lowest risk of resistance appears to be tenofovir (TDF). However there are several questions that remain unanswered regarding the use of TDF, including the proportion of patients that achieves suppression of HBV viral load and over what time, whether suppression is durable and whether prior treatment with other HBV-active drugs such as lamivudine, compromises the efficacy of TDF due to possible selection of resistant HBV strains. Methods A systematic review and meta-analysis following PRISMA guidelines and using multilevel mixed effects logistic regression, stratified by prior and/or concomitant use of lamivudine and/or emtricitabine. Results Data was available from 23 studies including 550 HBV/HIV coinfected patients treated with TDF. Follow up was for up to seven years but to ensure sufficient power the data analyses were limited to three years. The overall proportion achieving suppression of HBV replication was 57.4%, 79.0% and 85.6% at one, two and three years, respectively. No effect of prior or concomitant 3TC/FTC was shown. Virological rebound on TDF treatment was rare. Interpretation TDF suppresses HBV to undetectable levels in the majority of HBV/HIV coinfected patients with the proportion fully suppressed continuing to increase during continuous treatment. Prior treatment with 3TC/FTC does not compromise efficacy of TDF treatment. The use of combination treatment with 3TC/FTC offers no significant benefit over TDF alone.

Do HIV Care Providers Appropriately Manage Hepatitis B in Coinfected Patients Treated with Antiretroviral Therapy

Hepatitis C virus (HCV) monoinfection has been linked to type 2 diabetes mellitus (DM). We evaluated the effect of HCV on risk of DM in relation to traditional risk factors such as age, body mass index (BMI) and family history of DM in an HIV‐infected population.

Role of ribavirin in HCV treatment response: now and in the future

BACKGROUND The common occurrence of hepatitis B virus (HBV) infection in patients who carry the human immunodeficiency virus (HIV) demands that both viruses be recognized, evaluated, and treated when appropriate. METHODS We identified 357 HIV- and hepatitis B surface antigen-positive patients who underwent testing from 1999 to 2003; 155 patients who were new to our clinic and who initiated therapy for HIV and HBV coinfection were considered for inclusion in the study. The frequency of HIV testing (to determine HIV load and CD4+ cell count) performed during the first year of therapy was compared with the frequency of HBV measurements (to determine hepatitis B e antigen, antibody to hepatitis B e antigen, and HBV load), abdominal ultrasound examination, and measurement of levels of alpha-fetoprotein in serum. RESULTS HBV load data were obtained for only 16% of patients before initiation of antiretroviral therapy (ART), whereas HIV load was determined for 99% of patients before initiation of ART. The total number of HIV load measurements obtained during the first year after ART initiation was 497 (median number of HIV load measurements per patient, 3.0), compared with 85 measurements of HBV load (median number of HBV load measurements per patient, <1; P<.001). The percentage of patients who received any level of HBV monitoring (i.e., tests to determine hepatitis B e antigen, antibody to hepatitis B e antigen, and HBV load) after ART initiation increased from 7% in 1999 to 52% in 2001 (P<.001), whereas the percentage of patients who underwent HIV load testing remained at 80%-90% during the same period. CONCLUSIONS Health care providers treating patients with HIV infection during the period 1999-2003 infrequently monitored HBV response in coinfected patients, but they systematically monitored HIV response after ART initiation. Improved physician adherence to guidelines that better delineate HBV treatment and monitoring for patients with HIV-HBV coinfection is needed.

Evolution of hepatitis C virus NS5A region in breakthrough patients during pegylated interferon and ribavirin therapy

Importance of the field: Ribavirin is a broad spectrum antiviral agent that is used with pegylated IFN (Peg-IFN) for HCV treatment. Ribavirin does not significantly reduce HCV viral load when used alone but increases rates of sustained virologic response (SVR) when combined with Peg-IFN. HCV genotype 1 infected patients require higher doses of ribavirin administered for a longer duration of time versus HCV genotypes 2 and 3 patients who respond effectively to Peg-IFN with lower doses of ribavirin and shorter duration of therapy. Higher serum concentrations of ribavirin are associated with higher response rates but also higher rates of hemolytic anemia which is a dose limiting side effect. Alternatives to current therapy are under clinical evaluation. Areas covered in this review: Systematic literature review of ribavirin use in HCV patients from 1995 to 2009 was conducted. What the reader will gain: To review the efficacy and safety of ribavirin in current HCV treatment and in new therapies in Phase III clinical trials. Take home message: Ribavirin is a drug which is essential to produce higher SVR rates both with Peg-IFN and HCV protease inhibitors currently in Phase III clinical trials. Thus, ribavirin is and will remain an important drug to achieving higher SVR rates in HCV infected persons.