Predicted Coronary Heart Disease Risk in Croatian HIV Infected Patients Treated with Combination Antiretroviral Therapy

We assessed the coronary heart disease (CHD) risk in 130 HIV-infected patients with no major past cardiovascular event treated with combination antiretroviral therapy (CART) between May 2004 and June 2005. We also investigated the association of HIV disease parameters (CD4+ T-cell counts, HIV viral load, AIDS diagnosis, antiretroviral medications and lipodystrophy), demographics, anthropometrics, clinical features, smoking status, dyslipidemia, adherence to the Mediterranean diet, and the metabolic syndrome (MS) to the Framingham risk score. The median 10-year CHD risk was 6.4% (IQR 3.3–13.0) for males and 1.8% (IQR 1.0–6.7) for females. The CHD risk was ³10% in 31.1% (32 of 103) males and in 14.8% (4 of 27) females. MS was present in 27 (20.8%) individuals. Participants who met the definition of the MS had a 2.63 times greater chance of having a CHD risk ³10% (95% CI, 1.09–6.39; p=0.032). On multivariable analysis, we found that a CHD risk ³10% was associated with: a lowest ever CD4+ T-cell counts of less than 50 per microliter and a past history of AIDS (OR, 6.26; 95% CI, 1.61–24.36; p=0.008); alcohol consumption ³10 g/day (OR, 3.87; 95% CI, 1.56–14.22; p=0.041); and age ³43 years (OR, 1.30; 95% CI, 1.17–1.45; p<0.001). Interventions to reduce the modifiable cardiovascular risk are needed in Croatian patients treated with CART

Initial Therapy of Human Immunodefi ciency Virus Infection in 2009

Liječenje je zaraze virusom humane imunodeficijencije (HIV od engl. human immunodeficiency virus) i nakon više od jednog desetljeća primjene učinkovito. Usprkos tomu što nije potkrijepljeno randomizirnim kliničkim pokusom, današnje smjernice preporučuju ranije započinjanje antiretrovirusnog liječenja. Naime, mnoga opservacijska istraživanja uz analize kliničkog pokusa SMART pokazuju da je morbiditet i mortalitet u asimptomatskih osoba s CD4+ limfocitima T između 200 i 350/mm3 značajan. Uz to postoji povezanost nekontroliranog umnožavanja HIV-a s imunosnom aktivacijom koja je pak povezana s ne-AIDS-morbiditetom i mortalitetom. Smjernice iz razvijenih zemalja govore u prilog individualnom pristupu liječenju, a Svjetska zdravstvena organizacija zalaže se za javnozdravstveni pristup (definirane kombinacije prve i druge linije). U Hrvatskoj se primjenjuje individualni pristup, no on je ograničen manjim izborom antiretrovirusnih lijekova u odnosu na razvijene države. Većina smjernica u početnom liječenju preporučuje kombinacije analoga nukleozida(tida) tenofovir/emtricitabin ili abakavir/lamivudin. Dok se prema pojedinim smjernicama prednost daje nenukleozidnim analozima, većina daje mogućnost izbora između nenukleozidnih analoga i inhibitora proteaze u početnom liječenju. Od nenukleozidnih analoga, prema većini smjernica danas se daje prednost efavirenzu u odnosu na nevirapin. Inhibitori proteaze se danas daju isključivo s niskim dozama ritonavira. Izbor je u većini smjernica relativno velik i uključuje primjenu atazanavira, fosamprenavira, darunavira, lopinavira i sakvinavira.The treatment of human immunodeficiency virus (HIV) infections is still effective after more than a decade of antiretroviral drug usage. Current guidelines recommend the earlier initiation of treatment despite the fact that there is no such evidence from a randomized clinical trial. However, many observational studies and data from the SMART study showed significant morbidity and mortality rates in asymptomatic patients with CD4+ lymphocyte T counts between 200 and 350 per mm3. Additionally, there is an association between uncontrolled HIV replication, immune activation and non-AIDS morbidity and mortality. Guidelines from developed countries are recommending an individual approach to treatment initiation whereas the World Health organization (WHO) endorses a public health approach (with defined combinations for the first and second line regimens). In Croatia we are implementing an individual approach, but with limited choices of treatment options compared to developed countries. Most guidelines recommend to initiate the treatment with a combination of nucleoside(tide) analogues such as tenofovir/emtricitabine or abacavir/lamivudine. According to some guidelines, the initiation of treatment with non nucleoside analogues is preferred; however, the majority of guidelines have no clear preference between the classes of non-nucleoside analogues and protease inhibitors. The majority of guidelines prefer efavirenz to nevirapine. Protease inhibitors are only given with low-dose ritonavir. Most guidelines recommend a number of protease inhibitors: atazanavir, fosamprenavir, darunavir, lopinavir and saquinavir

Predicted Coronary Heart Disease Risk in Croatian HIV Infected Patients Treated with Combination Antiretroviral Therapy

We assessed the coronary heart disease (CHD) risk in 130 HIV-infected patients with no major past cardiovascular event treated with combination antiretroviral therapy (CART) between May 2004 and June 2005. We also investigated the association of HIV disease parameters (CD4+ T-cell counts, HIV viral load, AIDS diagnosis, antiretroviral medications and lipodystrophy), demographics, anthropometrics, clinical features, smoking status, dyslipidemia, adherence to the Mediterranean diet, and the metabolic syndrome (MS) to the Framingham risk score. The median 10-year CHD risk was 6.4% (IQR 3.3–13.0) for males and 1.8% (IQR 1.0–6.7) for females. The CHD risk was ³10% in 31.1% (32 of 103) males and in 14.8% (4 of 27) females. MS was present in 27 (20.8%) individuals. Participants who met the definition of the MS had a 2.63 times greater chance of having a CHD risk ³10% (95% CI, 1.09–6.39; p=0.032). On multivariable analysis, we found that a CHD risk ³10% was associated with: a lowest ever CD4+ T-cell counts of less than 50 per microliter and a past history of AIDS (OR, 6.26; 95% CI, 1.61–24.36; p=0.008); alcohol consumption ³10 g/day (OR, 3.87; 95% CI, 1.56–14.22; p=0.041); and age ³43 years (OR, 1.30; 95% CI, 1.17–1.45; p<0.001). Interventions to reduce the modifiable cardiovascular risk are needed in Croatian patients treated with CART

Antiretroviral Treatment of Adult Patients in the 2004

Nove informacije i novi lijekovi za liječenje infekcije uzrokovane virusom humane imunodeficijencije tipa 1 proširili su naše mogućnosti, ali i dileme u pogledu izbora lijekova, započinjanja i mijenjanja liječenja. Za 2004. godinu preporučujemo započeti liječenje: 1) svim osobama sa simptomima, 2) asimptomatskim osobama s manje od 200 CD4+ limfocita T u mm3 i 3) asimptomatskim osobama koje imaju CD4+ limfocite T između 200 i 350 po mm3 s više od 60 000 kopija HIV1 RNK u ml plazme ili su imale izraženiji pad CD4+ limfocita T (više od 80 stanica u jednoj godini). Ne preporučuje se antiretrovirusno liječenje ako je broj CD4+ limfocita T iznad 350 po mm3. Preporučuje se primjena nenukleozidnog analoga ili inhibitora proteaze potpomognutog niskim dozama ritonavira, s dva nukleozidna analoga. Temeljem dosadašnjih kontroliranih randomiziranih kliničkih pokusa preporučuje se inicijalna primjena efavirenza ili lopinavira potpomognutog ritonavirom. Kombinacije koje uključuju tri analoga nukleozida ne preporučuju se u početnom liječenju. Uspješnost liječenja mjeri se postizanjem nemjerljive viremije (manje od 50 kopija HIV1 RNK u ml plazme). U slučaju uspješnog početnog liječenja ono se može ili zbog želje bolesnika ili nuspojava modificirati jednostavnijim i manje toksičnim kombinacijama. U slučaju neuspjeha početnog liječenja treba obratiti osobitu pažnju na suradljivost bolesnika, rezistenciju HIV-a i farmakokinetiku lijekova. U slučaju virološkog neuspjeha potrebno je testirati otpornost HIV-a na lijekove i primijeniti lijekove na temelju tog nalaza.New information and new drugs for the treatment of human immunodeficiency virus type 1 infection have expanded our options but also dilemmas on the choice of drugs, onset and change of treatment. For the year 2004 we recommend starting treatment for: 1) patients with symptomatic HIV disease, 2) asymptomatic patients with less than 200 CD4+ cell counts per mm3 of blood, and 3) asymptomatic patients with CD4+ cell counts between 200 and 350 per mm3 of blood, and a HIV1 RNA viral load greater than 60000 copies per ml of plasma or a rapidly declining CD4+ cell count (more than 80 cells per mm3 in one year). We do not recommend treatment for asymptomatic patients with more than 350 CD4+ cells per mm3. The initial treatment should include a non-nucleoside analogue or a boosted protease inhibitor supported by low doses of ritonavir, with two nucleoside analogues. On the basis of randomized controlled clinical trials performed so far, the initial treatment of efavirenz or lopinavir/ritonavir can be recommended. The combination of three nucleoside analogues is not recommended for initial treatment. Treatment success is defined by achieving a non-measurable viremia (less than 50 copies of HIV1 RNA per ml plasma). In the case of successful treatment, the antiretroviral regimen can be modified by simpler and less toxic combinations due to either the patient’s wish or adverse events. In the case of initial therapy failure, special attention should be paid to issues like compliance, HIV virus resistance and drug pharmacokinetics. If the drug fails, it is necessary to test HIV virus resistance to drugs and adequate medication should be administered on the basis of this analysis

TREATMENT OF CHRONIC HEPATITIS C IN HUMAN IMMUNODEFICIENCY VIRUS INFECTED PATIENTS

Liječenje HCV-infekcije u osoba zaraženih HIV-om pruža mogućnost eradikacije virusa tako da je svaka osoba s mjerljivom viremijom kandidat za liječenje. Liječe se koinficirane osobe koje imaju: 1) opetovano povišene vrijednosti alanin aminotransferaze, 2) stupanj fibroze F2 i veći bez obzira na vrijednosti aminotransferaza, i 3) više od 200 limfocita CD4+ u μL krvi. Ne liječe se osobe koje aktivno konzumiraju ilegalne droge, veće količine alkohola i boluju ili su bolovale od teže neuropsihijatrijske bolesti. Preporuča se liječenje kombinacijom pegiliranog interferona i ribavirina prilagođenog tjelesnoj težini (1000 mg/dan za 75 kg). Primjenjuje se pegilirani interferon (doza za alfa-2a oblik: 180 μg supkutano jednom tjedno; doza za alfa2-b oblik: 1,5 μg/kg/tjedan). HCV RNK potrebno je odrediti nakon 4 tjedna liječenja, a potom prema potrebi nakon 12, 24, 48 i 72 tjedna. Da bi se evaluirao održani virološki odgovor potrebno je odrediti HCV-RNK 24 tjedna nakon završetka liječenja. Bolesnici koji imaju brzi virusološki odgovor (nedetektabilna razina HCV RNK nakon 4 tjedna liječenja) liječe se u trajanju od 24 (genotipovi 2 i 3) ili 48 tjedana (genotipovi 1 i 4). Bolesnici koji nemaju brzi odgovor, ali imaju povoljan odgovor nakon 12. i 24. tjedna liječenja, liječe se 48 tjedana. Bolesnicima koji imaju smanjenje viremije 75 kg) is recommended. Pegylated interferon is used as 180 μg for the alfa-2a form and 1.5 mg/kg for the alfa-2b form once weekly subcutaneously. HCV RNA should be measured after 4 weeks of treatment, and later as needed, in weeks 12, 24, 48 or 72. For evaluation of a sustained virologic response, HCV RNA should be measured 24 weeks after the end of treatment. Treatment duration for patients who have a rapid viral response (undetectable levels of HCV RNA after 4 weeks of treatment) is 24 weeks (genotypes 2 and 3) or 48 weeks (genotypes 1 and 4). For patients without a rapid virologic response, but with an adequate response after 12 and 24 weeks, we generally recommend treatment for 48 weeks. Treatment discontinuation is recommended for patients with <2 log viral load decline after 12 weeks or with a detectable viral load after 24 weeks of treatment. In HCV genotype 1 infection and F3 or F4 liver fibrosis, treatment with boceprevir or telaprevir in addition to pegylated interferon and ribavirin is recommended. In case of persistent HCV replication during therapy stopping rules should be applied

Reverzibilnost lipoatrofije u HIV-om zaraženih bolesnika na antiretrovirusnoj terapiji: kohortna studija s ultrazvučnim praćenjem

The aim of this study was to characterize and compare changes in subcutaneous fat in the malar, brachial and crural region in a cohort of HIV-infected patients taking antiretroviral therapy. This prospective longitudinal study included 77 patients who were selected from the initial cohort evaluated in 2007 and 2008. We examined reversibility of lipoatrophy measured by ultrasound over at least five-year period and factors related to its reversibility. All 46 patients who used stavudine switched from stavudine to another combination. Of 58 patients on zidovudine, 16 (28%) were on a zidovudine based regimen at the second follow up. There was evidence for subcutaneous fat increase in the malar area (p<0.001) and no increase in the brachial and crural areas. Patients who were smokers and had poor adherence to the Mediterranean diet had a thinner malar area at the follow up measurement (p=0.030) and smaller increase in subcutaneous malar fat compared to others (p=0.040). Our study suggested that modest increase of subcutaneous fat in malar area coincided with stopping stavudine and fewer usage of zidovudine. Lifestyle with non-adherence to the Mediterranean diet and smoking were associated with a smaller increase in subcutaneous malar fat.Cilj ovog istraživanja bio je okarakterizirati i usporediti promjene potkožnog masnog tkiva na licu, nadlaktici i potkoljenici u skupini HIV-om zaraženih bolesnika koji uzimaju antiretrovirusne lijekove. Radi se o prospektivnoj longitudinalnoj studiji u koju je bilo uključeno 77 bolesnika koji su odabrani iz početne kohorte koja je evaluirana 2007. i 2008. godine. Istraživali smo reverzibilnost lipoatrofije mjerene ultrazvukom u razdoblju od najmanje pet godina i čimbenike povezane s tom reverzibilnošću. Kod svih 46 bolesnika koji su uzimali stavudin on je zamijenjen nekom drugom kombinacijom lijekova. Od 58 bolesnika koji su uzimali zidovudin 16 (28%) ih je uzimalo kombinacije temeljene na zidovudinu kod kontrolnog mjerenja. Dokazan je porast potkožne masti na licu (p<0,001), dok na nadlaktici i potkoljenici nije bilo porasta. Bolesnici koji su bili pušači i slabo su se pridržavali mediteranske dijete imali su tanje potkožno masno tkivo na licu kod kontrolnog mjerenja (p=0,030), kao i manji porast potkožne masti na licu u usporedbi s ostalima (p=0,040). Naše istraživanje upućuje na to da se blaži porast potkožne masti na licu podudara s prestankom uzimanja stavudina i manjim uzimanjem zidovudina. Način života uz nepridržavanje mediteranske dijete i pušenje bio je povezan s manjim porastom potkožne masti na licu

Toxicity-related antiretroviral drug treatment modifications in individuals starting therapy: a cohort analysis of time patterns, sex, and other risk factors.

BackgroundModifications to combination antiretroviral drug therapy (CART) regimens can occur for a number of reasons, including adverse drug effects. We investigated the frequency of and reasons for antiretroviral drug modifications (ADM) during the first 3 years after initiation of CART, in a closed cohort of CART-naïve adult patients who started treatment in the period 1998-2007 in Croatia.Material and methodsWe calculated differential toxicity rates by the Poisson method. In multivariable analysis, we used a discrete-time regression model for repeated events for the outcome of modification due to drug toxicity.ResultsOf 321 patients who started CART, median age was 40 years, 19% were women, baseline CD4 was &lt;200 cells/mm3 in 71%, and viral load was ≥100 000 copies/mL in 69%. Overall, 220 (68.5%) patients had an ADM; 124 (56%) of these had ≥1 ADM for toxicity reasons. Only 12.7% of individuals starting CART in the period 1998-2002 and 39.4% in the period 2003-2007 remained on the same regimen after 3 years. The following toxicities caused ADM most often: lipoatrophy (22%), gastrointestinal symptoms (20%), and neuropathy (18%). Only 5% of drug changes were due to virologic failure. Female sex (hazard ratio [HR], 2.42 95%; confidence intervals, 1.39-4.24) and older age (HR, 1.42 per every 10 years) were associated with toxicity-related ADM in the first 3 months of a particular CART regimen, but after 3 months of CART they were not.ConclusionsLess toxic and better-tolerated HIV treatment options should be available and used more frequently in Croatia

Ponovljena prezentacija Gravesove bolesti kao manifestacije sindroma imune rekonstitucije u bolesnice zaražene HIV-om koja uzima antiretrovirusne lijekove

An HIV-infected patient who experienced immune reconstitution after highly active antiretroviral therapy (HAART) (increase in CD4 T-cell count from 84/mm3 to 310/mm3) presented with severe Graves’ disease twice, after commencing and recommencing HAART. At the first episode of Graves’ disease, 21 months after the introduction of HAART, the symptoms of thyroid dysfunction vanished without any specific treatment, but were associated with termination of taking HAART. At the second episode, 5 years after recommencing HAART, the patient continued taking HAART and commenced antithyroid therapy with thiamazole. Graves’ disease developed after a long period, while the patient was in good condition and when complications resulting from HAART were not expected. No features of any autoimmune disease were diagnosed before HAART initiation.Bolesnica zaražena HIV-om u koje se razvio sindrom imune rekonstitucije nakon antiretrovirusnog liječenja (ARL) (porast broja stanica CD4 s 84/mm3 na 310/mm3) prezentirala se u dva navrata s Gravesovom bolešću, na početku liječenja ARL-om i nakon stanke u liječenju. Tijekom prve epizode 21 mjesec nakon uvođenja ARL-a simptomi tiroidne disfunkcije nestali su bez specifičnog liječenja, ali su bili povezani s prestankom uzimanja ARL-a. Tijekom druge epizode 5 godina nakon ponovnog uzimanja ARL-a bolesnica je nastavila uzimati ARL i započela s antitiroidnim lijekom tiamazolom.Gravesova bolest se ponovno javila nakon dugog razdoblja kad je bolesnica bila u dobrom općem stanju i kad se komplikacije vezane uz ARL više nisu očekivale. Prije uzimanja ARL-a bolesnica nije pokazivala nikakve znakove autoimune bolesti