Influence of SLCO1B1 polymorphisms on lopinavir Ctrough in Serbian HIV/AIDS patients.

AIMS: Lopinavir (LPV) is not a first-line regimen. According to recent WHO data, LPV usage in low- and middle-income countries accounted for approximately 52% of the adult and 23% of the paediatric protease inhibitor market in 2017. Since LPV is a substrate for the SLCO1B1 (OATP1B1) transporter, the aim of this study was to assess the impact of SLCO1B1 polymorphisms (rs11045819, rs4149032 and rs4149056) on LPV trough plasma concentrations (Ctrough ) in Serbian patients. METHODS: Plasma samples from 104 HIV/AIDS Caucasians were collected. LPV Ctrough was quantified using liquid-chromatography-mass spectrometry. Genotyping was carried out using real-time-PCR-based allelic discrimination. One-way analysis of variance, t test and linear regression were used for data analysis. RESULTS: The overall mean (SD) LPV Ctrough was 5885 ± 2755 ng/mL. Significant differences were between patients with different rs11045819 genotypes: CC (LPV median Ctrough = 6072 ng/mL, interquartile range (IQR) = 4318-7617 ng/mL), CA (LPV median Ctrough = 4987 ng/mL, IQR = 4300-6295 ng/mL) and AA (LPV median Ctrough = 3648 ng/mL, IQR = 1949-4072 ng/mL) (P = .005). Significant differences were also observed according to rs4149032 genotype: CC (LPV median Ctrough = 6027 ng/mL, IQR =4548-8250 ng/mL), CT (LPV median Ctrough = 5553 ng/mL, IQR = 4300-6888 ng/mL) and TT (LPV median Ctrough = 4408 ng/mL, IQR = 3361-5233 ng/mL) (P = .007). For rs4149056 a statistically significant difference between T-homozygotes (LPV median Ctrough = 5434 ng/mL, IQR = 3855-6830 ng/mL), heterozygotes (LPV median Ctrough = 6707 ng/mL, IQR = 5088-8063 ng/mL) and C-homozygotes (LPV median Ctrough = 13906 ng/mL, IQR = 12946-14866 ng/mL) was observed (P = .002). In multivariate regression analysis, only the SLCO1B1 rs4149056 polymorphism was independently associated with higher LPV Ctrough (ß = 2834.5 [1442-4226.9] ng/mL [P = .001]). CONCLUSIONS: Our results demonstrate a statistically significant influence of the SLCO1B1 rs4149056 polymorphism on higher LPV Ctrough in Caucasian HIV/AIDS patients.

Severe hepatotoxicity induced by efavirenz in a treatment-naïve, low body mass index HIV-infected, female patient with no hepatitis and other virus co-infections.

Combined antiretroviral therapy (cART) consisting of two nucleoside reverse transcriptase inhibitors (NRTIs) and one non-nucleoside reverse transcriptase inhibitor (NNRTI), such as efavirenz, is still the first-line treatment in resource-limited settings. However, efavirenz has shown strong prominence of disadvantages with variance in plasma concentration and central nervous side effects. Our study presents HIV infected, drug naïve, female patient with relatively low BMI, CYP2B6 516G>T (rs3745274) genotype with high efavirenz plasma concentration. In this case report, the patient was admitted at the hospital 6 months after cART initiation with drug-induced severe hepatotoxicity. Furthermore, pathophysiological findings proved confluent parenchymal necrosis after aspiration liver biopsy, with mild to moderate inflammation in portal tracts with focal interface hepatitis. All other possible causes were excluded. Thus, we conclude that efavirenz has a potential harmful effect in patients with low BMI, specific genotyping and interindividual pharmacokinetics affecting high plasma concentration.

Lower levels of IL-4 and IL-10 influence lipodystrophy in HIV/AIDS patients under antiretroviral therapy.

BACKGROUND: The role of interleukins in the pathogenesis of lipodystrophy in HIV/AIDS-patients is still not understood. The aim of this study was to evaluate the relationship between serum levels of interleukins between HIV/AIDS-patients with or without lipodystrophy, as well as between different subgroups of lipodystrophy (lipoatrophy, lipohypertrophy, mixed-fat-redistribution) and patients without lipodystrophy. METHODS: Cross-sectional study of 66 HIV/AIDS patients, all Caucasians. Serum levels of interleukins (IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, IL-10) were measured using Cytokine-Array-1 on Evidence Investigator, Biochip Array Technology. The associations between interleukins and anthropometric and metabolic variables were estimated by Spearman-correlation. Analysis of covariance with bootstrapping method (ACBM) was used to examine relationship between interleukins and lipodystrophy categories adjusted for confounding variables. RESULTS: The lipodystrophy was observed in 29 (44%) patients, while 15 (52%) had lipoatrophy, 4 (14%) lipohypertrophy and 10 (34%) patients had mixed fat redistribution. There were 37 (56%) patients without lipodystrophy. Significantly lower levels of IL-4 and IL-10 were observed in lipodystrophy vs. non-lipodystrophy (p=0.008; p=0.027, respectively). No differences were found relating IL-1α, IL-1ß, IL-2, IL-6 and IL-8 levels in lipodystrophy vs. non-lipodystrophy. In patient subgroup with lipoatrophy, significantly lower levels of IL-4 and IL-10 were found when compared to non-lipodystrophy (p=0.043; p=0.031, respectively). In lipohypertrophy subgroup significantly lower levels of IL-4 were found when compared to non-lipodystrophy (p=0.003). In order to estimate the correlation of IL-4 and IL-10 and the presence of lipodystrophy, ACBM showed that correlation of IL-4 levels in patients with lipodystrophy remains statistically significant (p=0.004) in all types of lipodystrophy: lipoatrophy, lipohypertrophy and mix-fat-redistribution (p=0.027; p=0.009; p=0.017, respectively) after adjustment for age, BMI. CONCLUSIONS: IL-4 and IL-10 levels were significantly lower in lipodystrophy vs. non-lipodystrophy. According to our knowledge, we showed for the first time significant correlation between IL-4 levels and lipodystrophy development in HIV/AIDS patients.

Treatment outcomes of first-line antiretroviral therapy in HIV-1-positive patients in Serbia.

INTRODUCTION: Access to combination antiretroviral treatment (cART) and toxicity profiles of antiretroviral medications have significantly improved during the last three decades. In order to optimise treatment outcomes, achieve favourable virological suppression and immunological status, balanced with potential adverse effects of cART, it is considered beneficial to maintain first-line antiretroviral treatment for as long as possible. However, the Republic of Serbia, as a resource-limited setting, often experiences interruptions to drug supplies. Data are very limited in Serbia concerning the initial antiretroviral regimens prescribed and the reasons for treatment changes. AIMS: The aim of this study was to determine the most frequently prescribed antiretroviral drugs within first-line cART regimens in drug-naïve patients in Serbia and the reasons for switching drugs. METHODS: All HIV-infected individuals who started cART at the HIV/AIDS Center of Infectious and Tropical Diseases, Clinical Centre of Serbia, from 1 January 2004 until 1 July 2014 were included. A cohort of 339 patients were retrospectively analysed to review their initial treatment regimens. All analyses were performed using the SPSS statistical package version 11.0. Descriptive measurements and Kaplan-Meier survival curves were used. RESULTS: The most frequently prescribed nucleoside reverse transcriptase inhibitor (NRTI) backbones in the cART regiment were fixed combinations of abacavir and lamivudine (n=181, 53.3%) and of zidovudine and lamivudine (n=103, 30.5%). Efavirenz was the most commonly prescribed 'third' drug (n=254, 75%). Where given, reasons for switching initial cART were shortage of antiretroviral drugs (e.g. out of stock, n=53, 37.6%), toxicity (n=49, 34.3%), physician choice (n=21, 14.6%), resistance (n=15, 10.6%), and patient choice (n=4, 2.9%). Mean duration of first-line cART was 20±17 months. CONCLUSION: The most frequently prescribed initial cART regimen in Serbia is not the preferred first choice, but an alternative option according to the international antiretroviral treatment guidelines. Duration of first-line cART is short and a switch to second-line cART is often made due to a shortage of antiretroviral medications and the more severe side effects resulting from the use of older drugs.

Choice of first-line antiretroviral therapy regimen and treatment outcomes for HIV in a middle income compared to a high income country: a cohort study.

BACKGROUND: The range of combination antiretroviral therapy (cART) regimens available in many middle-income countries differs from those suggested in international HIV treatment guidelines. We compared first-line cART regimens, timing of initiation and treatment outcomes in a middle income setting (HIV Centre, Belgrade, Serbia - HCB) with a high-income country (Royal Free London Hospital, UK - RFH). METHODS: All antiretroviral-naïve HIV-positive individuals from HCB and RFH starting cART between 2003 and 2012 were included. 12-month viral load and CD4 count responses were compared, considering the first available measurement 12-24 months post-cART. The percentage that had made an antiretroviral switch for any reason, or for toxicity and the percentage that had died by 36 months (the latest time at which sufficient numbers remained under follow-up) were investigated using standard survival methods. RESULTS: 361/597 (61 %) of individuals initiating cART at HCB had a prior AIDS diagnosis, compared to 337/1763 (19 %) at RFH. Median pre-ART CD4 counts were 177 and 238 cells/mm(3) respectively (p < 0.0001). The most frequently prescribed antiretrovirals were zidovudine with lamivudine (149; 25 %) and efavirenz [329, 55 %] at HCB and emtricitabine with tenofovir (899; 51 %) and efavirenz [681, 39 %] at RFH. At HCB, a median of 2 CD4 count measurements in the first year of cART were taken, compared to 5 at RFH (p < 0.0001). Median (IQR) CD4 cell increase after 12 months was +211 (+86, +359) and +212 (+105, +318) respectively. 287 (48 %) individuals from HCB and 1452 (82 %) from RFH had an available viral load measurement, of which 271 (94 %) and 1280 (88 %) were <400 copies/mL (p < 0.0001). After 36 months, comparable percentages had made at least one antiretroviral switch (77 % HCB vs. 78 % RFH; p = 0.23). However, switches for toxicity/patient choice were more common at RFH. After 12 and 36 months of cART 3 % and 8 % of individuals died at HCB, versus 2 % and 4 % at RFH (p < 0.0001). CONCLUSION: In middle-income countries, cART is usually started at an advanced stage of HIV disease, resulting in higher mortality rates than in high income countries, supporting improved testing campaigns for early detection of HIV infection and early introduction of newer cART regimens.