Claudia Bernardini

Ultrasensitive assessment of residual low-level HIV viremia in HAART-treated patients and risk of virological failure.

Background:Low-level viremia (LLV) is measurable, with enhanced assays, in many subjects with HIV RNA levels <50 copies per milliliter. The clinical consequences of LLV are unknown. Methods:In a prospective study in HIV-1–infected adults, HIV RNA levels were determined with an ultrasensitive test (3 copies/mL) based on a real time polymerase chain reaction. The primary end point was to evaluate LLV prediction of virological failure, defined as a confirmed plasma HIV RNA level >50 copies per milliliter. Results:One thousand two hundred fourteen patients were followed for (mean) 378 days. At baseline, 71.5% were <3 copies per milliliter below the limit of detection (BLD). The risk of failing highly active antiretroviral therapy in the following 4 months for patients BLD was 0.4% compared with a 3.2% risk for those with LLV (P < 0.0001; odds ratio: 7.52). There was a significant (P < 0.0001) linear relationship between the HIV RNA and the risk of virologic failure. LLV receiver operating curve analysis showed an area under the curve of 0.76 (95% confidence interval: 0.68 to 0.84) that significantly (P < 0.0001) predicted the risk of failure. The risk of an unconfirmed viral blip was higher in patients with LLV (3.9%) than in those BLD (1.1%) (P < 0.0001; odds ratio: 3.56). Longer exposure to antiretrovirals, current use of nonnucleoside reverse transcriptase inhibitors, longer time BLD, and current HIV RNA <3 copies per milliliter were independent predictors of a positive outcome. Interpretation:Viral replication may be the cause of LLV, at least in some patients. A LLV >3 copies per milliliter is linked to a significant increment of risk of virological failure leading to drug resistance. Patients with measurable LLV should be managed to better evaluate, over time, the risk of failure and to limit its consequences.

Triple-combination rilpivirine, emtricitabine, and tenofovir (Complera™/Eviplera™) in the treatment of HIV infection

The combination rilpivirine (RPV)/emtricitabine (FTC)/tenofovir (TDF) is a once-daily, single-tablet regimen (STR) containing one nonnucleoside reverse-transcriptase inhibitor associated with two nucleos(t)ide reverse transcriptase inhibitors. It is approved by regulatory agencies (eg, US Food and Drug Association, European Medicines Agency) in all countries in which it is manufactured, except Switzerland, as first-line highly active antiretroviral therapy (HAART) for the treatment of naïve patients with HIV infection and a viral load HIV-RNA level of ≤100,000 copies/mL. Two large trials (ECHO and THRIVE) comparing RPV with efavirenz, along with different background regimens, led to approval of the drug, while a more recent trial (STaR) explored the use of STR. RPV showed noninferiority to efavirenz in all the studies, including superiority as an STR in patients with HIV-RNA ≤100,000 copies/mL in the STaR study. A positive CD4 cell response was observed in all the studies, both in the RPV and efavirenz groups. The incidence of virologic failures was higher for RPV, but was mostly referred to patients with HIV-RNA >100,000 copies/mL. There were fewer adverse events (AEs) with the RPV-based regimens versus efavirenz-based regimens, with a lower discontinuation rate because of AEs, especially psychiatric–neurological AEs, and a significantly lower rate of blood-lipid abnormalities. In the SPIRIT study (a switch study), significantly greater improvements from baseline in serum total cholesterol, low-density lipoprotein cholesterol, and trygliceride were demonstrated in patients switching to RPV/FTC/TDF from a ritonavir-boosted protease inhibitor (PI/r)-based regimen, than in those who continued treatment with a PI/r regimen. RPV’s better tolerability, associated with its once-daily STR formulation, is key to improving patients’ adherence and quality of life, which are among the most important factors affecting the therapeutic efficacy of an antiretroviral regimen. In summary, RPV/FTC/TDF STR is a valuable treatment option for the majority of antiretroviral-naïve HIV-infected patients. Furthermore, the use of this STR in the therapeutic switch, like in the SPIRIT study, can result in another valuable option by which to reduce AEs and improve patients’ quality of life.

Effectiveness of a project to prevent HIV vertical transmission in the Republic of Congo

OBJECTIVES To evaluate the effectiveness of a prevention programme against the vertical transmission of HIV in a resource-limited setting and to investigate variables associated with compliance. PATIENTS AND METHODS The Kento-Mwana project (2005-2008) provided counselling, serological and biomolecular testing and prophylaxis/therapy to HIV-positive pregnant women and their children attending four antenatal clinics in Pointe Noire, Republic of Congo. Expected and actual rates of vertical transmission of HIV were compared. Univariate and multivariate analyses were performed in order to identify variables associated with non-compliance. RESULTS The observed transmission rate in the group who completed follow-up was 5/290 (1.7%, 95% CI 0.6%-4.1%). The overall estimated transmission rate in the target population, computed taking into account the expected vertical transmission of HIV among drop-outs, was 67-115/638 (10.5%-18.0%). A comparison between this rate and the expected transmission rate in the absence of intervention (25%-40%) showed that the programme was able to prevent approximately 50% of vertical transmissions. Older age (OR 0.33, 95% CI 0.16-0.66, P = 0.002), telephone availability (OR 0.42, 95% CI 0.24-0.72, P = 0.002) and occupation (OR 0.57, 95% CI 0.29-1.10, P = 0.092) were associated with better compliance. CONCLUSIONS Despite the vast majority of women accepting counselling and testing, many of them refused prophylaxis or dropped out, thus reducing the effectiveness of the intervention from an ideal 2% to a still important but less impressive median transmission rate of 15% (range 10.5%-18%). Promoting participation and compliance, rather than increasing the potency of antiretroviral regimens, is crucial for preventing the vertical transmission of HIV in Africa.

Inflammation Markers Correlate With Common Carotid Intima-Media Thickness in Patients Perinatally Infected With Human Immunodeficiency Virus 1

OBJECTIVES To investigate common carotid intima-media thickness in a cohort of patients who were vertically infected with human immunodeficiency virus 1 (HIV-1). METHODS We conducted a cross-sectional observational study. Human immunodeficiency virus 1-infected patients were compared with age-, sex-, and body mass index-matched healthy participants. Common carotid intima-media thickness was measured in all participants on both sides of the neck, and the mean intima-media thickness was calculated. Metabolic parameters and markers of inflammation were measured only in HIV-1-infected patients. Statistical analysis was performed by multiple regression and by a matrix of Pearson correlation coefficients. The Student t test was used to compare mean common carotid intima-media thickness values between groups. RESULTS Forty patients (21 female) with HIV-1 infection acquired from birth with a mean age ± SD of 16.3 ± 4.7 years and 27 healthy participants (11 female) with a mean age of 17.7 ± 4.6 years were included in the study. Mean common carotid intima-media thickness in the HIV-1-infected group (0.450 ± 0.088 mm) was significantly higher (P < .05) than in the control group (0.407 ± 0.079 mm). No significant association was found between intima-media thickness and a specific antiretroviral regimen, exposure to combined antiretroviral agents, and HIV status. In multiple regression analyses, higher levels of insulin (P= .007) and elevated levels of glycated hemoglobin (P= .01) were associated with intima-media thickness changes. CONCLUSIONS Patients perinatally infected with HIV have increased common carotid intima-media thickness compared with healthy individuals. These changes were more pronounced with increasing age and inflammation markers. Interventions that improve cardiovascular risk profiles should be considered in HIV-infected young adults.

Safety and efficacy of pegylated interferon and ribavirin in adolescents with human immunodeficiency virus and hepatitis C virus acquired perinatally.

Limited evidence is available currently regarding the efficacy and safety of pegylated interferon (PEG‐IFN) and ribavirin in patients co‐infected perinatally with human immunodeficiency virus (HIV) and hepatitis C virus (HCV). No information is available on whether or not these patients should be treated earlier for infection with HCV. This report describes four patients with HIV and HCV co‐infection acquired perinatally, who were treated with PEG‐IFN and ribavirin for chronic viral hepatitis caused by HCV. J. Med. Virol. 82: 1110–1114, 2010.

Cost-effectiveness analysis of antiretroviral therapy in a cohort of HIV-infected patients starting first-line highly active antiretroviral therapy during 6 years of observation

Objectives Costs may play a role in deciding how and when to start highly active antiretroviral therapy (HAART) in a naïve patient. The aim of the present study was to assess the cost- effectiveness of treatment with HAART in a large clinical cohort of naïve adults to determine the potential role of single-tablet regimens in the management of patients with human immunodeficiency virus (HIV). An incremental cost-effectiveness ratio analysis was performed, including a quality-adjusted life year approach. Results In total, 741 patients (females comprising 25.5%) were retrospectively included. The mean age was 39 years, the mean CD4 cell count was 266 cells/μL, and the mean viral load was 192,821 copies/mL. The most commonly used backbone was tenofovir + emtricitabine (77.6%); zidovudine + lamivudine was used in 10%, lamivudine + abacavir in 3%, and other nucleoside reverse transcriptase inhibitor (NRTI) or NRTI-free regimens in 9.4% of patients. NNRTIs were used in 52.8% of cases, boosted protease inhibitors in 44.1%, and unboosted protease inhibitors and integrase inhibitors in 0.7% and 2.4%, respectively. Starting therapy at CD4 >500 cells/μL and CD4 351–500 cells/μL rather than at <201 cells/μL was the more cost-effective approach. The same consideration was not true comparing current indications with the possibility to start HAART at any CD4 value (eg, >500 cells per μL); in this case, the incremental cost-effectiveness ratio value was €199,130 per quality-adjusted life year gained, a higher value than the one suggested in guidelines. The single-tablet regimen (STR) invariably dominated any other therapeutic approach. Sensitivity analysis was performed, and starting right away with an STR was cost-effective even when compared with therapeutic strategies contemplating STR as simplification. Conclusion By integrating clinical data with economic variables, our study offers an estimate of the cost-effectiveness of the various first-line treatment strategies for patients infected with HIV and provides significant evidence to be used in future prospective pharmacoeconomic evaluations.

Efficacy and safety of darunavir and etravirine in an antiretroviral multi-experienced youth with vertically HIV-1 infection

Multiclass-drug resistance, often caused by poor treatment compliance, is a challenging problem in all categories of HIV-infected patients. Selective pressure is higher in youth for both biological and behavioral reasons. We report the case of a 15-year-old Caucasian male, with vertically acquired HIV-1 infection, who failed several lines of antiretroviral therapy and was successfully treated with darunavir/ritonavir and etravirine.

Comment on: Residual viraemia does not influence 1 year virological rebound in HIV-infected patients with HIV RNA persistently below 50 copies/mL

349, p. 198. Foundation for Retrovirology and Human Health, Alexandria, VA, USA. 3 Doyle T, Smith C, Vitiello P et al. Plasma HIV-1 detection below 50 copies/mL and risk of virologic rebound in patients receiving highly active antiretroviral therapy. Clin Infect Dis 2012; 54: