Emanuela Lattuada

Progressive multifocal leukoencephalopathy in an HIV patient receiving successful long-term HAART.

Progressive multifocal leukoencephalopathy (PML) has been traditionally associated to severe immunosuppression and described mainly in highly active antiretroviral therapy (HAART)-naïve patients with a low lymphocyte CD4+ count. In the last years, some cases of PML have been described in HIV patients with a higher CD4+ count shortly after initiation of HAART and in association with the immune reconstitution inflammatory syndrome (IRIS). We report on a rare case of PML, not IRIS associated, that occurred in a HIV-positive patient with a lymphocyte CD4+ count greater than 700/µl and with an undetectable HIV viral load resulting from a long-term HAART. We describe the pathological and the ultrastructural features of the brain lesion. This case confirms that a severe immunosuppression or an IRIS is not required for the development of PML in HIV positives. The diagnosis of PML should always be considered in patients with consistent neurological symptoms, even with a high lymphocyte CD4+ level and a full viral suppression resulting from a long-term HAART.

Recreational substance use and tolerance of efavirenz in HIV-1 infected patients

Abstract During the past few years, efavirenz has been increasingly used in the treatment of HIV1 infection. Its main side effect is a syndrome of central nervous system stimulation occurring in 40–50% of adults in the first few weeks of therapy which might be observed at increased frequency in subjects concurrently using recreational substances. We therefore conducted a single center, retrospective study in 134 patients treated with efavirenz and found no significant differences in CNS side effects or discontinuation rates between recreational substance (cocaine, ecstasy, cannabis) users and non-users. Although our study is limited, the results support the idea that efavirenz can be safely prescribed to patients using recreational substances.

Efavirenz dose reduction in HIV-infected patients

First-line treatment with two nucleoside reverse transcriptase inhibitors (NRTIs) plus efavirenz (EFV) 600 mg daily is the standard of care in HIV infection. Some patients benefit from an EFV dose reduction, and a Phase II study carried out during the development of EFV supported use of a lower dose [1]. ENCORE 1, a randomized, blinded, placebo-controlled trial comparing EFV at the standard dose of 600 mg versus 400 mg in 630 patients treated for 48 weeks, has started [2], but results will not be available until 2013. We describe our experience of EFV dose reduction in a clinical setting (Infectious Diseases Outpatient Clinic, University of Verona, Verona, Italy) in 33 HIV-infected patients treated with two NRTIs plus EFV. Blood samples collected 9–16 hours after the last dose intake were stored for subsequent measurement of EFV plasma levels [3]. Three groups of patients were included in the study (Table 1). In group 1 patients, EFV was reduced to 400 mg after 33–119 months (mean 66.4 months) on the full dose and when HIV RNA was <50 HIV-1 RNA copies/mL. EFV was reduced, because of sleep disturbances and on the basis of pharmacokinetic data, to 400 mg in all but one patient (who switched to 200 mg). After a mean of 12.6 months, all the patients continue to have undetectable HIV RNA, and side effects have disappeared. Mean EFV plasma levels decreased by 65.9% at 6 months, and in five subjects the post-dose reduction EFV concentration was below 1000 ng/mL, i.e. the supposed minimum effective concentration (MEC) [4]. Group 2 patients had a mean treatment duration of 35.4 months (range 21–60 months) and HIV RNA <50 copies/mL before a reduction of EFV to 400 mg by the physicians in charge because of sleep disturbances and prior to having knowledge of the pharmacokinetic data. Ten to twelve months after the reduction of EFV, all patients continue to have undetectable HIV RNA, with no side effects. Mean EFV plasma levels decreased by 34.4% at 6 months, and in five subjects the post-dose reduction EFV concentration was below the MEC. Group 3 patients were naïve to antiretrovirals, and had a pretreatment mean HIV RNA level of 104 529 copies/mL. Four patients were started on EFV 400 mg by the physicians in charge, and four had decided to take only 400 mg and two only 200 mg despite being prescribed the full dose. The latter six patients informed physicians of their decision after a few months on the reduced doses, and then pharmacokinetic analysis was performed. After 9–86 (mean 30) months on reduced doses, all patients have undetectable HIV RNA. The mean EFV level was 1579.9 ng/mL at 6 months. Correspondence: Prof. Sandro Vento, Department of Internal Medicine, School of Medicine, Faculty of Health Sciences, University of Botswana, Private Bag 00713, Gaborone, Botswana. Tel: +267.3554177; fax: +267.3105979; e-mail: ventosandro@yahoo.it

Efficacy of a reduced dose of darunavir/ritonavir in a cohort of antiretroviral-naive and -experienced HIV-infected patients: a medium-term follow-up

Background: The currently approved dose of darunavir/ritonavir is 800/100 mg once daily for PI-naive patients, and 600/100 mg twice daily for PI-pretreated patients. However, in DRV-sensitive patients at baseline in the POWER 1/2 trials, similar rates of HIV RNA suppression (1 log reduction) were achieved with doses ranging from 400/100 mg once daily to 600/100 mg twice daily. In previously virologically suppressed patients, a reduced dose of DRV (600/100 QD) is non-inferior to the standard dose (800 mg QD)[1] and DRV concentrations in plasma and CSF are similar in patients receiving the above different doses [1,2]. Methods: Twelve treatment-naive patients were started on darunavir/ritonavir 600/100mg once daily, with TDF/FTC (8) or ABC/ 3TC (4). Seven patients were switched to darunavir/ritonavir 600/100 mg once daily, with TDF/FTC (2), ABC/3TC (2), NVP (1), AZT/3TC (1). One was on monotherapy with DRV. Seven treatment-experienced patients were switched to darunavir/ritonavir 600/100 mg once daily, with TDF/FTC (5), ABC/3TC (1), RAL (1). Results: Of the 12 naive patients (mean baseline HIV RNA 134,024 log10 copies/mL, range 4,256-397,932), 11 had HIV RNA B20 c/mL after a mean 27.4 months of follow-up (range 12 33). Mean PK level was 2,920 ng/mL (1,268 4,562). One patient had virological failure after 14 months (HIV RNA 39,300 copies/mL); no mutations were detected and after introduction of DRV/r 600 mg b.i.d., he returned aviremic. All switched patients maintained HIV RNA suppression (B20 c/mL) for a mean of 32.8 months (range 21-54). PK level was available for one patient only (Ctrough 3,442 ng/mL). Of the treatment-experienced patients (mean baseline HIV RNA 24,167 log10 copies/mL, range 112 111,426), five maintained HIV RNA suppression for a mean of 46.2 months (range 31 67). One patient interrupted HAART for three months and then restarted it, the latest HIV RNA level being 628 copies/mL after five weeks of therapy. One patient failed after 42 months (HIV RNA 3,930 copies/mL); after intensification (DRV/ r 600 twice daily), he returned aviremic. PK levels were available for three patients (mean 2,502 ng/mL; range 844 4,518). Conclusions: In this pilot study of 26 patients, use of DRV/r at 600/100 mg OD dose led to sustained HIV RNA suppression in 23 patients with acceptable PK exposures to DRV. Large non-inferiority trials are warranted to establish its efficacy.

Raltegravir: is a 400 mg once-daily dose enough?

coding regions of the transpeptidase domain of the pbp1a, pbp2b and pbp2x genes of the two GBS isolates were amplified and sequenced according to previously outlined methods. 4 Amino acid sequences were deduced and analysed using the ClustalW alignment tool included in the Lasergene software (DNAstar, Madison, WI, USA). Nucleotide and deduced amino acid sequences were compared with those of the reference penicillin-susceptible strains 2603V/R (GenBank accession number: NC_004116) and NEM316 (GenBank accession number: NC_004368). DNA analysis revealed that the pbp genes of the clinical GBS isolates possessed many amino acid substitutions compared with the corresponding genes of the reference strains 2603V/R and NEM316. Five previously described amino acid substitutions were observed in both the penicillin-susceptible GBS and penicillin G-non-susceptible GBS isolates (S453N and N682D in PBP1a, V625I in PBP2b, and I377V and G627V in PBP2x). 4 However, there were three novel substitutions (T526A in PBP1a, P278L in PBP2b and N575D in PBP2x) found exclusively in the penicillin G-non-susceptible GBS 2007 isolate. In previous studies, the V405A and Q557E substitutions adjacent to the conserved SSN and KSG motifs in PBP2x, considered to form the active site of the enzyme, were found in 4 invasive GBS with elevated, but still susceptible, MICs of one or multiple b-lactam antibiotics, in 21 penicillin G-non-susceptible GBS isolated from the respiratory tract and in a penicillin G-non-susceptible GBS recurrently isolated from a sacral ulcer. 2 – 5 Several amino acid substitutions in PBP1a, PBP2a and PBP2b were also found in penicillin G-non-susceptible GBS isolated from the respiratory tract. 4 However, the PBP2a amino acid substitutions were documented in only two GBS with penicillin MICs of 1 mg/L. 4 In the present study, the penicillin G-non-susceptible GBS 2007 isolate did not harbour the PBP2x V405A and Q557E substitutions previously associated with reduced susceptibility to penicillin. 2 – 5 Instead, the penicillin G-non-susceptible GBS 2007 isolate possessed three novel substitutions (T526A in PBP1a, P278L in PBP2b and N575D in PBP2x). At this time it is not known whether these substitutions can actually increase resistance to penicillin since they were not found within or in the proximity of the putative conserved motifs, and their significance needs to be assessed in future studies. Moreover, it is possible that the penicillin G-non-susceptible GBS 2007 isolate harboured mutations in other pbp or non-pbp genes that are responsible for the observed phenotype. To our knowledge, that is the first report of development …

A maintenance dose of atazanavir/ritonavir 200/100 mg once daily is effective in virologically suppressed HIV-1-infected patients.

To the Editors: Schipani et al, in their recent simulation study, concluded that 300/50 mg and 200/100 mg once daily dosing are preferred candidate regimens in future clinical studies of atazanavir/ritonavir combination. Elevated values of hyperbilirubinemia, a common side effect of atazanavir, are associated with a Ctrough of atazanavir higher than the minimum efficacy concentration (MEC) of 150 ng/mL. Previous small studies in Thai patients have indeed shown the efficacy and safety of switching from a conventional atazanavir/ritonavir dose (300/100 mg once daily) to a lower dose of atazanavir (200 mg once daily with the booster of ritonavir) in patients who had a viral load below 50 copies per milliliter for several weeks. We report our own results in an “induction/ maintenance” antiretroviral strategy where a low dose of atazanavir/ritonavir (200/ 100 mg once daily) allowed maintenance of long-term viral suppression in a small cohort of HIV-1–infected patients. In October 2011, we selected of the 51 patients on atazanavir/ritonavir (300/100 mg once daily) in combination with a backbone in the Outpatient Clinic of the Infectious Unit of the University of Verona, the 14 patients (10 whites and 4 black Africans) on their first antiretroviral regimen with the following characteristics: undetectable plasma HIV-RNA (below 50 copies/mL) for at least 6 months, no resistance protease mutations at baseline genotypic test, and no hepatitis B virus or hepatitis C virus coinfection. All patients gave written informed consent and we reduced the dose of atazanavir/ritonavir to 200/100 mg once daily and performed a pharmacokinetic analysis after 6 months on the reduced dose. Atazanavir plasma concentrations were measured using a validated high performance liquid chromatography assay at the antiretroviral drugs’ Clinical Pharmacology Laboratory, “Amedeo di Savoia” Hospital, Turin. All the patients were taking atazanavir in the morning on full stomach, and blood samples were drawn after 24 hours from the last dose. The patients’ main features are shown in Table 1. Ctrough of atazanavir at reduced dose was higher than the suggested MEC for atazanavir (150 ng/mL) in all but 2 patients.

Intracranial mass lesions in HIV/AIDS patients from developing countries endemic for neurocysticercosis.

In HIV-infected patients neurological signs and symptoms can be frequent first clinical presentations; the detection of intracranial mass lesions on computed tomography (CT) or magnetic resonance imaging (MRI) is a frequent problem because of difficult diagnosis and management. Opportunistic infections such as Mycobacterium tubercolosis Toxoplasma gondii Cryptococcus neoformans as well as primary central nervous system lymphoma can show the same radiological imaging. Correct diagnosis is necessary to prescribe appropriate therapy and also to obviate the need for neurosurgical intervention. Smego et al. have presented a simplified and therapeutic algorithm for approaching intracranial mass which is useful for both developed and resourced-limited countries. The algorithm is based upon CD4+ lymphocyte count specific serology chest X-ray neuroradiology and routine lumbar puncture study. We would also like to underline the possibility of inserting in these screenings serological testing for Neurocysticercosis at least for patients coming from developing countries of Central and South America sub-Saharan Africa and east and south Asia where the disease is endemic. (excerpt)

Dolutegravir monotherapy in HIV-infected naive patients with an HIV-RNA load <100 000 copies/mL: a medium-term follow-up

linezolid before introduction of tedizolid. Interestingly, in two cases, though we immediately introduced tedizolid after linezolid interruption, we noted the rapid correction of myelotoxicity and no subsequent new toxicity despite a prolonged use of tedizolid (9 and 12 weeks, respectively) for two patients. The myelotoxicity of oxazolidinones is not well explained, but seems to be linked to mitochondrial toxicity. Since tedizolid exhibits a greater, but shorter, inhibition of mitochondrial protein synthesis than linezolid, this, combined with a lower total daily dose (200 mg daily versus 1200 mg daily), could explain the noticeable absence of myelotoxicity for tedizolid at current doses. Indeed, a recent study in healthy subjects has shown that higher daily doses of tedizolid (300 and 400 mg daily) seem to induce thrombocytopenia as frequently as linezolid. Finally, microbiological cure was obtained with tedizolid for the two infections that were documented. Other works will have to confirm the long-term haematological safety of tedizolid, but we believe there is no need for any washout period after linezolid-induced myelotoxicity, as demonstrated in two of our three patients.

Efficacy of a reduced dose of DARUNAVIR/RTV in a cohort of antiretroviral-naïve and experienced HIV-infected patients: a medium-term follow-up.

The currently approved dose of darunavir/ritonavir is 800/100 mg once daily for PI‐naïve patients, and 600/100 mg twice daily for PI‐pretreated patients. However, in DRV‐sensitive patients at baseline in the POWER 1/2 trials, similar rates of HIV RNA suppression (1 log reduction) were achieved with doses ranging from 400/100 mg once daily to 600/100 mg twice daily. In previously virologically suppressed patients, a reduced dose of DRV (600/100 QD) is non‐inferior to the standard dose (800 mg QD)[ 1 ] and DRV concentrations in plasma and CSF are similar in patients receiving the above different doses [ 1 , 2 ].

A reduced dose of darunavir/ritonavir is effective in PI-experienced HIV-infected patients

Darunavir (DRV) is an HIV-1 protease inhibitor that is used together with a low boosting dose of ritonavir as part of an antiretroviral therapy (ART) regimen in treatment-experienced and naïve HIV-positive patients. In naïve and experienced patients with no DRV-mutations, DRV is licensed at the dose of 800 mg plus 100 mg of ritonavir once daily. We report our results in seven ART-experienced HIV-infected patients, in whom a reduced dose of darunavir/ritonavir (600/100 mg once daily) successfully controlled viral replication.