Transmission of Human Immunodeficiency Virus I Drug Resistance - a Case Report. What are the Clinical Implications?

The success of first-line antiretroviral therapy can be challenged by the acquisition of primary drug resistance. Here we report a case where baseline genotypic resistance testing detected resistance conferring nucleoside/nucleotide reverse transcriptase inhibitor (NRTI)-associated mutations, but no primary mutations for protease inhibitor (PI). Subsequent PI-based HAART with boosted saquinavir led to virological treatment success with persistently undetectable viral load. After treatment simplification from saquinavir to an atazanavir based PI-therapy and no change in backbone therapy rapid virological breakthrough occurred. Retrospective analysis displayed preexisting gag cleavage site mutations which may have reduced the genetic barrier in a clinical relevant manner in combination with the already existing NRTI resistance mutations. Alternatively, this effect could be explained with a different antiviral potency for the respective PIs used

Cancer risk in HIV-infected individuals on HAART is largely attributed to oncogenic infections and state of immunocompetence

<p>Abstract</p> <p>Objectives</p> <p>To estimate the cancer risk of HIV-infected patients in the HAART era with respect to a general reference population and to determine risk factors for malignancy.</p> <p>Methods</p> <p>Long term (1996-2009) cancer incidence of the Bonn single centre HIV cohort was compared to the incidence of the reference population of Saarland using standardized incidence ratios (SIR). Poisson regression analysis was used to identify predictors of cancer risk.</p> <p>Results</p> <p>1,476 patients entered the cohort, enabling 8,772 person years of observation. 121 tumours in 114 patients, 7 in-situ and 114 invasive cancers, were identified. Malignancies associated with infectious agents such as Kaposi sarcoma (SIRs: male: 5,683; female: 277), non-Hodgkin lymphoma (SIRs male: 35; female: 18), anal cancer (SIRs male: 88; female: 115) as well a cervical carcinoma (SIR female: 4) and Hodgkin's disease (SIR male: 39) and liver cancer (SIR male: 18) were substantially more frequent in HIV-infected patients than in the general population (p < 0.001, each), whereas all other types of cancer were not increased. Poisson regression identified HAART (incidence rate ratio IRR (95% CI): 0.28 (0.19-0.41), p < 0.001), CD4 count (IRR per 100 cells/μl increase: 0.66 (0.57-0.76), p < 0.001), hepatitis B (IRR: 2.15 (1.10-4.20), p = 0.046) and age (IRR per 10 year increase: 1.23 (1.03 - 1.46), p = 0.023) as independent predictors for the occurrence of any type of cancer.</p> <p>Conclusions</p> <p>HAART and preserved CD4 cells preferentially reduce the risk of malignancies associated with oncogenic infections.</p

Beyond viral suppression of HIV – the new quality of life frontier

BACKGROUND: In 2016, the World Health Organization (WHO) adopted a new Global Health Sector Strategy on HIV for 2016–2021. It establishes 15 ambitious targets, including the ‘90-90-90’ target calling on health systems to reduce under-diagnosis of HIV, treat a greater number of those diagnosed, and ensure that those being treated achieve viral suppression. DISCUSSION: The WHO strategy calls for person-centered chronic care for people living with HIV (PLHIV), implicitly acknowledging that viral suppression is not the ultimate goal of treatment. However, it stops short of providing an explicit target for health-related quality of life. It thus fails to take into account the needs of PLHIV who have achieved viral suppression but still must contend with other intense challenges such as serious non-communicable diseases, depression, anxiety, financial stress, and experiences of or apprehension about HIV-related discrimination. We propose adding a ‘fourth 90’ to the testing and treatment target: ensure that 90 % of people with viral load suppression have good health-related quality of life. The new target would expand the continuum-of-services paradigm beyond the existing endpoint of viral suppression. Good health-related quality of life for PLHIV entails attention to two domains: comorbidities and self-perceived quality of life. CONCLUSIONS: Health systems everywhere need to become more integrated and more people-centered to successfully meet the needs of virally suppressed PLHIV. By doing so, these systems can better meet the needs of all of their constituents – regardless of HIV status – in an era when many populations worldwide are living much longer with multiple comorbidities

Progression of liver fibrosis in HIV/HCV genotype 1 co-infected patients is related to the T allele of the rsI2979860 polymorphism of the IL28B gene

<p>Abstract</p> <p>Objective</p> <p>HIV/HCV co-infection is characterised by accelerated progression of liver disease. Recently, the rsl2979860 C/T polymorphism in the <it>IL28B </it>gene has been linked to progression towards cirrhosis in HCV mono-infected patients and to treatment response of HCV-infection in HIV/HCV co-infected patients. Our aim was to clarify by non-invasive techniques if this polymorphism affects fibrosis progression in HIV/HCV co-infection.</p> <p>Methods</p> <p>In a cross-sectional design, liver stiffness (transient elastography), surrogate markers of liver fibrosis (APRI and FIB-4 scores) and rsl2979860 genotypes were analysed in 84 HCV/H1V co-infected patients. <it>IL28B </it>genotypes were determined by real-time PCR using a light cycler. In 56 HIV/HCV co-infected patients we also studied progression of fibrosis in relation to rsl2979860 C/T genotypes over two years.</p> <p>Results</p> <p>82% of the patients were on HAART (74% without detectable HI viremia) and 67% were haemophiliacs, respectively. HCV genotype 1 was present in 62%. Cross-sectional median liver stiffness was 7.4 kPa and correlated with APRI and FIB-4 scores (r = 0.6 each, p < 0.001). Frequencies of <it>IL28B </it>genotypes were: CC 50%, CT 43% and TT 7%. In the cross-sectional analysis liver stiffness values were not different between the various <it>IL28B</it>-genotypes. Upon follow-up under HAART carriers of a C allele did not show further progression, while liver stiffness significantly increased in HIV/HCV co-infected patients with the T allele (p = 0.047).</p> <p>Conclusion</p> <p>Although progression of liver fibrosis was low under HAART in our cohort, progression was more pronounced in HIV/HCV genotype 1 co-infected patients with the T allele.</p

Safety and Efficacy of Ombitasvir, Paritaprevir With Ritonavir ± Dasabuvir With or Without Ribavirin in Patients With Human Immunodeficiency Virus-1 and Hepatitis C Virus Genotype 1 or Genotype 4 Coinfection: TURQUOISE-I Part 2.

BACKGROUND: Ombitasvir, paritaprevir with ritonavir, and dasabuvir (OBV/PTV/r ± DSV) ±ribavirin (RBV) are approved to treat hepatitis C virus (HCV) genotype 1 and 4 infection. Here, we investigate the safety and efficacy of OBV/PTV/r + DSV ±RBV for HCV genotype 1, and OBV/PTV/r + RBV for HCV genotype 4, in human immunodeficiency virus (HIV)-1 coinfected patients with or without compensated cirrhosis. METHODS: TURQUOISE-I, Part 2 is a phase 3 multicenter study. Patients with or without cirrhosis were HCV treatment-naive or -experienced, on an HIV-1 antiretroviral regimen containing atazanavir, raltegravir, dolutegravir, or darunavir (for genotype 4 only), and had plasma HIV-1 ribonucleic acid <40 copies/mL at screening. Patients received OBV/PTV/r ± DSV ±RBV for 12 or 24 weeks. RESULTS: In total, 228 patients were treated according to guidelines. Sustained virologic response at posttreatment week 12 (SVR12) was achieved by 194 of 200 (97%) and 27 of 28 (96%) patients with HCV genotype 1 and genotype 4 infection, respectively. There were 2 virologic failures: 1 breakthrough and 1 relapse in a cirrhotic and a noncirrhotic patient with genotype 1b and 1a infection, respectively. One reinfection occurred at posttreatment week 12 in a genotype 1a-infected patient. Excluding nonvirologic failures, the SVR12 rates were 98% (genotype 1) and 100% (genotype 4). Adverse events were mostly mild in severity and did not lead to discontinuation. Laboratory abnormalities were rare. CONCLUSIONS: The OBV/PTV/r ±DSV was well tolerated and yielded high SVR12 rates in patients with HCV genotype 1 or genotype 4/HIV-1 coinfection. The OBV/PTV/r ± DSV ±RBV is a potent HCV treatment option for patients with HIV-1 coinfection, regardless of treatment experience

Hepatotoxicity and effectiveness of a Nevirapine-based antiretroviral therapy in HIV-infected patients with or without viral hepatitis B or C infection in Cameroon

Background: Coinfection with hepatitis B virus (HBV) or hepatitis C virus (HCV) in HIV-infected patients receiving a commonly used nevirapine-based antiretroviral therapy is a major concern for African clinicians owing to its high prevalence, the infrequent testing and treatment of viral hepatitis, and the impact of liver disease on the tolerability and effectiveness of anti-HIV treatment. We compared the hepatotoxicity and the immunological, virological and clinical effectiveness of a nevirapine-based antiretroviral therapy between patients infected with HIV only and patients coinfected with hepatitis B or C virus in Cameroon. Methods: A retrospective cohort study was conducted among HIV-1-infected patients. Plasma HBV DNA and HCV RNA were tested in positive or indeterminate samples for HBsAg or HCV antibodies, respectively. All patients received nevirapine and lamivudine plus stavudine or zidovudine. Results: Of 169 HIV-1-infected patients with a median baseline CD4 count of 135 cells/mm(3) (interquartile range [IQR] 67 218), 21% were coinfected with HBV or HCV. In coinfected patients, the median viral load was 2.47 x 107 IU/mL for HBV (IQR 3680-1.59 x 10(8)) and 928 000 IU/mL for HCV (IQR 178 400-2.06 x 10(6)). Multivariate analyses showed that the risk of hepatotoxicity was 2-fold higher in coinfected patients (p < 0.01). The response to antiretroviral therapy was however comparable between monoinfected and coinfected patients in terms of CD4 cell count increase (p = 0.8), HIV-1 viral load below 400 copies/mL (p = 0.9), death (p = 0.3) and death or new AIDS-defining event (p = 0.1). Nevirapine was replaced by a protease inhibitor in 4 patients owing to hepatotoxicity. Conclusion: This study suggests that the nevirapine-based antiretroviral therapy could be used safely as first-line treatment in patients with low CD4 cell count in Africa despite frequent coinfections with HBV or HCV and infrequent testing of these infections. Although testing for HBV and HCV should be systematically performed before initiating antiretroviral therapy, transaminases elevations at baseline or during treatment should be a decisive argument for testing when hepatitis status is unknown

Clinical Outcomes in Persons Coinfected With Human Immunodeficiency Virus and Hepatitis C Virus: Impact of Hepatitis C Virus Treatment

Background: A hepatitis C (HCV) cure is associated with changes in lipids and inflammatory biomarkers, but its impact on clinical endpoints among treated human immunodeficiency virus (HIV)/HCV coinfected persons is unclear. / Methods: People living with HIV from EuroSIDA with a known HCV status after January 2001 were classified into strata based on time-updated HCV RNA measurements and HCV treatment, as either HCV antibody–negative; spontaneously resolved HCV; chronic, untreated HCV; cured HCV (HCV RNA–negative); or HCV treatment failures (HCV RNA–positive). Poisson regression was used to compare incidence rates between HCV groups for end-stage liver disease (ESLD; including hepatocellular carcinoma [HCC]), non–acquired immunodeficiency virus defining malignancy (NADM; excluding HCC), and cardiovascular disease (CVD). / Results: There were 16 618 persons included (median follow-up 8.3 years, interquartile range 3.1–13.7). There were 887 CVD, 902 NADM, and 436 ESLD events; crude incidence rates/1000 person-years follow-up were 6.4 (95% confidence interval [CI] 6.0–6.9) for CVD, 6.5 (95% CI 6.1–6.9) for NADM, and 3.1 (95% CI 2.8–3.4) for ESLD. After adjustment, there were no differences in incidence rates of NADM or CVD across the 5 groups. HCV-negative individuals (adjusted incidence rate ratio [aIRR] 0.22, 95% CI 0.14–0.34) and those with spontaneous clearance (aIRR 0.61, 95% CI 0.36–1.02) had reduced rates of ESLD compared to cured individuals. Persons with chronic, untreated HCV infections (aIRR 1.47, 95% CI 1.02–2.13) or treatment failure (aIRR 1.80, 95% CI 1.22–2.66) had significantly raised rates of ESLD, compared to those who were cured. / Conclusions: Incidences of NADM or CVD were independent of HCV group, whereas those cured had substantially lower incidences of ESLD, underlining the importance of successful HCV treatment for reducing ESLD

Clinical use of HIV integrase inhibitors : a systematic review and meta-analysis

Background: Optimal regimen choice of antiretroviral therapy is essential to achieve long-term clinical success. Integrase inhibitors have swiftly been adopted as part of current antiretroviral regimens. The purpose of this study was to review the evidence for integrase inhibitor use in clinical settings. Methods: MEDLINE and Web-of-Science were screened from April 2006 until November 2012, as were hand-searched scientific meeting proceedings. Multiple reviewers independently screened 1323 citations in duplicate to identify randomized controlled trials, nonrandomized controlled trials and cohort studies on integrase inhibitor use in clinical practice. Independent, duplicate data extraction and quality assessment were conducted. Results: 48 unique studies were included on the use of integrase inhibitors in antiretroviral therapy-naive patients and treatment-experienced patients with either virological failure or switching to integrase inhibitors while virologically suppressed. On the selected studies with comparable outcome measures and indication (n = 16), a meta-analysis was performed based on modified intention-to-treat (mITT), on-treatment (OT) and as-treated (AT) virological outcome data. In therapy-naive patients, favorable odds ratios (OR) for integrase inhibitor-based regimens were observed, (mITT OR 0.71, 95% CI 0.59-0.86). However, integrase inhibitors combined with protease inhibitors only did not result in a significant better virological outcome. Evidence further supported integrase inhibitor use following virological failure (mITT OR 0.27; 95% CI 0.11-0.66), but switching to integrase inhibitors from a high genetic barrier drug during successful treatment was not supported (mITT OR 1.43; 95% CI 0.89-2.31). Integrase inhibitor-based regimens result in similar immunological responses compared to other regimens. A low genetic barrier to drug-resistance development was observed for raltegravir and elvitegravir, but not for dolutegravir. Conclusion: In first-line therapy, integrase inhibitors are superior to other regimens. Integrase inhibitor use after virological failure is supported as well by the meta-analysis. Careful use is however warranted when replacing a high genetic barrier drug in treatment-experienced patients switching successful treatment

Predictors of mortality in HIV-associated hospitalizations in Portugal: a hierarchical survival model

<p>Abstract</p> <p>Background</p> <p>The beneficial effects of highly active antiretroviral therapy, increasing survival and the prevention of AIDS defining illness development are well established. However, the annual Portuguese hospital mortality is still higher than expected. It is crucial to understand the hospitalization behaviour to better allocate resources. This study investigates the predictors of mortality in HIV associated hospitalizations in Portugal through a hierarchical survival model.</p> <p>Methods</p> <p>The study population consists of 12,078 adult discharges from patients with HIV infection diagnosis attended at Portuguese hospitals from 2005–2007 that were registered on the diagnosis-related groups' database.</p> <p>We used discharge and hospital level variables to develop a hierarchical model. The discharge level variables were: age, gender, type of admission, type of diagnoses-related group, related HIV complication, the region of the patient's residence, the number of diagnoses and procedures, the Euclidean distance from hospital to the centroid of the patient's ward, and if patient lived in the hospital's catchment area. The hospital characteristics include size and hospital classification according to the National Health System. Kaplan-Meier plots were used to examine differences in survival curves. Cox proportional hazard models with frailty were applied to identify independent predictors of hospital mortality and to calculate hazard ratios (HR).</p> <p>Results</p> <p>The Cox proportional model with frailty showed that male gender, older patient, great number of diagnoses and pneumonia increased the hazard of HIV related hospital mortality. On the other hand tuberculosis was associated with a reduced risk of death. Central hospital discharge also presents less risk of mortality.</p> <p>The frailty variance was small but statistically significant, indicating hazard ratio heterogeneity among hospitals that varied between 0.67 and 1.34, and resulted in two hospitals with HR different from the average risk.</p> <p>Conclusion</p> <p>The frailty model suggests that there are unmeasured factors affecting mortality in HIV associated hospitalizations. Consequently, for healthcare policy purposes, hospitals should not all be treated in an equal manner.</p