Claudia Bianco

Treatment of HCV infection with the novel NS3/4A protease inhibitors.

HCV NS3/4A serine protease inhibitors are the first class of direct acting antivirals (DAA) introduced in clinical practice. The first generation agents, selective against HCV genotype 1, are used in association with pegylated interferons and ribavirin allowing increased cure rates at the price of increased toxicity, significant drug interactions and high risk of selecting mutants conferring cross-resistance to the entire class. A large number of second-wave HCV protease inhibitors are currently in clinical development. Advancements include higher potency, activity against a wider number of genotypes, improved tolerability, easier dosing schedules, although their genetic barrier to resistance remains low, especially for subtype 1a, except for the most recent grazoprevir and ACH-2684. The most relevant progress regards the combination with other classes of DAA allowing construction of interferon-free regimens of short duration, good tolerability with exceptionally high cure rates.

Prevalence of HIV-1 integrase mutations related to resistance to dolutegravir in raltegravir naïve and pretreated patients.

The prevalence of HIV-1 integrase mutations related to resistance to the next-generation integrase inhibitor (INI), dolutegravir (DTG), was assessed in 440 INI-naïve subjects and in 120 patients failing a raltegravir (RTG)-containing regimen. Of the mutations selected by DTG in vitro, S153FY was not detected in any isolate while L101I and T124A were highly prevalent in both groups and significantly associated with non-B subtype. RTG-selected double and triple mutants, mostly the G140S/Q148H variant, were detected in only 32 (26.7%) RTG-treated patients. As L101I and T124A do not appear to exert any major effect in vivo and double and triple mutants resistant to DTG are infrequently selected by RTG, DTG can be effectively used in INI-naïve patients and may retain activity in many patients failing RTG.

Safety and therapeutic efficacy of the switch to maraviroc+darunavir/ritonavir in HIV/HCV coinfected patients: initial results from GUSTA study.

HIV/HCV coinfection is a risk factor for hepatic injury in patients receiving HAART and previous studies support a favourable effect of antiretroviral regimens including maraviroc (MVC) on the course of coinfection compared with other antiretroviral drugs. There are few observations about MVC use in simplified treatment of coinfected patients.Objective: To evaluate the efficacy and the safety of simplification to darunavir (DRV)/ritonavir (r)/maraviroc (MVC) in virologically HIV‐suppressed patients and to explore the effect of simplified treatment on coinfected patients.

Bone mineral density improvement after 48 weeks of switch to maraviroc+darunavir/ritonavir 300/800/100 mg QD, preliminary results of GUSTA study

Low bone mineral density (BMD) and osteoporosis are prevalent in HIV‐infected patients and were associated with HIV infection and tenofovir‐containing ART.

Switch to raltegravir-based regimens and HIV DNA decrease in patients with suppressed HIV RNA

Raltegravir intensification is associated with an increase in 2‐LTR episomal HIV DNA= circles, indicating a persistent low‐level replication, in some individuals in ART with suppressed HIV RNA. We aimed at monitoring residual plasma HIV RNA and cellular HIV DNA in virologically suppressed patients switching to a raltegravir‐based regimen.

Total cellular HIV-1 DNA decreases after switching to raltegravir-based regimens in patients with suppressed HIV-1 RNA

BACKGROUND The integrase inhibitor raltegravir has been used to intensify antiretroviral therapy in patients with undetectable plasma HIV-1RNA, resulting in variable perturbation of HIV-1 nucleic acids levels in peripheral blood. OBJECTIVES We aimed at monitoring residual plasma HIV-1RNA and total cellular HIV-1DNA in virologically suppressed patients switching to raltegravir-based regimens. STUDY DESIGN Fifty-eight subjects on protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens, with plasma HIV-1RNA levels <40 copies/ml for ≥6 months and CD4 counts >200cells/μl for ≥12 months were enrolled. Thirty-four patients were from the treatment simplification RASTA randomized study switching standard therapy to a raltegravir-based regimen (RASTA group), while 24 continued a PI or NNRTI based-regimen (controls). Residual plasma HIV-1RNA (5-40copies/mL) and HIV-1DNA were assessed at 0, 24 and 48 weeks. RESULTS At week 0 (W0), HIV-1DNA was detected in all patients while at W48 it was detectable in 82.4% of the RASTA group vs 100% of controls (p=0.03). There was a significant decline of HIV-1DNA at W48 in the RASTA group (mean change from baseline -0.21 [95% CI -0.41; -0.01] log10 copies/106 CD4; p=0.03) but not in controls. Ultrasensitive HIV-1RNA was detectable at baseline in 50% of RASTA group vs 67% of controls and at W48 in 32.4% vs 42%, respectively. No differences were found between HIV-1RNA levels at baseline and W48 within and between groups. CONCLUSIONS Switching successful therapy to raltegravir-based regimens may be associated with a decrease of the HIV-1 reservoir, as measured by peripheral blood cellular HIV-1DNA levels.

Hepatitis B virus surface antigen seroconversion after pegylated interferon-alpha treatment in an HIV-infected individual with chronic hepatitis B

Worldwide, approximately 36 million people live with the human immunodeficiency virus (HIV) and 370 million with the hepatitis B virus (HBV). The prevalence of chronic hepatitis B (CHB) infection in individuals with HIV varies between 5 and 20%, with higher levels found in areas in which CHB is endemic, such as countries in Africa and Asia [1]. Coinfection with HBV and HIV is common due to overlapping routes of transmission and is accompanied by an increased risk for liver-related morbidity and mortality [2]. Indeed, liver disease has emerged as one of the most important causes of morbidity and mortality among HIV-positive individuals after the introduction of highly active antiretroviral therapy (HAART), mainly in patients coinfected with either HBV or hepatitis C virus (HCV) [3]. HBV treatment is based on pegylated interferon-alpha (INF-a) or nucleos(t)ide polymerase inhibitors. While the former treatment has a finite duration and may be associated with durable response in terms of HBV control after its discontinuation, the latter requires life-long treatment to achieve chronic viral suppression. We report the case of a 42-year-old homosexual man presenting with positive HIV-1 serology at first observation in July 1995. His medial history was negative for HBV or HCV infection; he was a smoker, his body mass index was 30 kg/m, and he was diagnosed to have CDC stage A2 HIV. Due to high CD4 counts (range 410–1,352/lL) he was never prescribed antiretrovirals during the subsequent follow-up. In July 2002 the laboratory tests showed elevated liver enzymes, with alanine aminotransferase (ALT) at 527 IU/ml and aspartate aminotransferase (AST) at 204 IU/mL; the other biochemical liver function test values were normal. He was positive for hepatitis B surface antigen (HBsAg), hepatitis Be antigen (HBeAg), and antibodies to hepatitis B core antigen (anti-HBc) and negative for anti-hepatitis Be antibody (anti-HBe); HBV DNA was 200,000 IU/mL. Antibodies for HCV and hepatitis A virus (HAV) were negative. HIV infection was still well controlled, with plasma HIV-1 RNA at 1,960 copies/mL and a CD4 ? cell count of 626/lL (24%). The subsequent laboratory tests showed a normalization of liver enzymes and the persistence of HBsAg (Fig. 1). The HBsAg level were not quantified. In September 2005, because of the persistence of HBsAg and elevated ALT, therapy with pegylated INF-a2a 180 lg weekly was initiated and continued until April 2006 (28 weeks). At treatment initiation, plasma HBV DNA was 2.5 million IU/mL, his CD4 ? lymphocyte count was 1,352/lL (53%), and HIV-1 RNA was 8,560 copies/mL. After 19 weeks of treatment, the patient seroconverted from HBeAg to anti-HBe; at the 22th week, HBV DNA became undetectable (detection limit 60 IU/mL). During the entire follow-up period the patient did not require antiretroviral treatment. In April 2009, we observed HBsAg clearance (last positive HBsAg tested in February 2008) and the appearance of anti-HBs (74.6 mLU/mL), the last negative determination of which had been performed in February 2007. This result was confirmed in five subsequent controls, with last result obtained in April 2011 showing normal liver enzymes, negative HBsAg and HBeAg, HBV DNA \12 IU/mL, and positive anti-HBc, anti-HBe, and anti-HBs at 33 mIU/mL (Fig. 1). The lower probability of spontaneous loss of HBeAg or HBsAg in HIV/HBV-coinfected patients is due to impaired host innate and adaptive immunity [4]. In this patient with persistently high CD4 counts and an HBeAg-positive CHB, B. Rossetti (&) C. Bianco A. De Luca Second Division of Infectious Diseases, Policlinico Le Scotte, University of Siena, Viale Bracci 16, 53100 Siena, Italy e-mail: barbararossetti@libero.it