Switching to Doravirine in cART-Experienced Patients: An Effective and Highly Tolerated Option With Substantial Cost Savings.

BACKGROUND: Doravirine is a non-nucleoside reverse transcriptase inhibitor with demonstrated efficacy as a third agent in treatment-naive and treatment-experienced people living with HIV (PLWH) in registration studies. However, limited real-world data are available. METHODS: By searching electronic health care records, PLWH using doravirine-based regimens were selected with at least 1 year of follow-up after their first prescription. All stable PLWH who were switched to a doravirine-based regimen were included in the analysis. The primary outcome was the durability of a doravirine-based regimen 1 year after prescription. Reasons for stopping were also collected. Secondary outcomes for PLWH continuing a doravirine-based regimen after 1 year were routine laboratory assessment, body mass index, and differences in medication costs compared with their previous cART. RESULTS: A total of 687 patients (92% men) were included from September 2019 to August 2022: 97.7% switched to doravirine/tenofovir/lamivudine (DOR/TDF/3TC). After 1 year, 94/687 (13.6%) PLWH stopped this therapy. The main reason for discontinuation was patient-reported adverse events in 70/687 (10.2%). Medical reasons for discontinuation included increased alanine tranaminase levels in 6/687 (0.9%), decreased estimated glomerular filtration rate in 3/687 (0.4%), and precautions after diagnosis of osteoporosis in 2/687 (0.3%) patients. Virologic failure occurred in 4/687 cases (0.6%), and 1 case demonstrated resistance mutations. The secondary outcomes demonstrated a statistically significant increase in alanine tranaminase levels and decrease in LDL-c levels. The switch to a doravirine-based regimen in the Netherlands reduced medication costs by 27%. CONCLUSIONS: This study demonstrated that switching to a doravirine-based regimen, mostly DOR/TDF/3TC, was highly effective and generally well tolerated, with substantial cost savings.

Impact of switching from zidovudine to tenofovir disoproxil fumarate on bone mineral density and markers of bone metabolism in virologically suppressed HIV-1 infected patients; a substudy of the PREPARE study.

CONTEXT: In virologically suppressed, antiretroviral-treated patients, the effect of switching to tenofovir (TDF) on bone biomarkers compared to patients remaining on stable antiretroviral therapy is unknown. METHODS: We examined bone biomarkers (osteocalcin [OC], procollagen type 1 amino-terminal propeptide, and C-terminal cross-linking telopeptide of type 1 collagen) and bone mineral density (BMD) over 48 weeks in virologically suppressed patients (HIV RNA < 50 copies/ml) randomized to switch to TDF/emtricitabine (FTC) or remain on first-line zidovudine (AZT)/lamivudine (3TC). PTH was also measured. Between-group differences in bone biomarkers and associations between change in bone biomarkers and BMD measures were assessed by Student's t tests, Pearson correlation, and multivariable linear regression, respectively. All data are expressed as mean (SD), unless otherwise specified. RESULTS: Of 53 subjects (aged 46.0 y; 84.9% male; 75.5% Caucasian), 29 switched to TDF/FTC. There were reductions in total hip and lumbar spine BMD in those switching to TDF/FTC (total hip, TDF/FTC, -1.73 (2.76)% vs AZT/3TC, -0.39 (2.41)%; between-group P = .07; lumbar spine, TDF/FTC, -1.50 (3.49)% vs AZT/3TC, +0.25 (2.82)%; between-group P = .06), but they did not reach statistical significance. Greater declines in lumbar spine BMD correlated with greater increases in OC (r = -0.28; P = .05). The effect of TDF/FTC on bone biomarkers remained significant when adjusted for baseline biomarker levels, gender, and ethnicity. There was no difference in change in PTH levels over 48 weeks between treatment groups (between-group P = .23). All biomarkers increased significantly from weeks 0 to 48 in the switch group, with no significant change in those remaining on AZT/3TC (between-group, all biomarkers, P < .0001). CONCLUSION: A switch to TDF/FTC compared to remaining on a stable regimen is associated with increases in bone turnover that correlate with reductions in BMD, suggesting that TDF exposure directly affects bone metabolism in vivo.

Low bone mineral density, regardless of HIV status, in men who have sex with men.

A high prevalence of low bone mineral density (BMD) has been reported among men with primary or chronic human immunodeficiency virus (HIV) infection. To gain further insight into the contribution of HIV infection, we compared the BMD of 41 men who have sex with men (MSM) with primary HIV infection, 106 MSM with chronic HIV infection, and a control group of 30 MSM without HIV infection. Low BMD, defined as a z score of ≥ 2.0 SDs below the mean at the lumbar spine or hip, was highly prevalent in all 3 groups. In the multivariate analyses, HIV infection was not associated with BMD, suggesting that low BMD previously reported in HIV-infected MSM may predate HIV acquisition.

A comparison of measured and estimated glomerular filtration rate in successfully treated HIV-patients with preserved renal function.

BACKGROUND: Monitoring of renal function becomes increasingly important in the aging population of HIV-1 infected patients. We compared Cockroft & Gault (C&G), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), Modification of Diet in Renal Disease (MDRD), Cystatin C- and 24 h urine-based estimated GFR (eGFR) with the gold standard, measured GFR (mGFR) using [125I]-iothalamate. METHODS: Substudy within a randomized, multinational trial comparing continuing zidovudine/ lamivudine with switching to tenofovir/ emtricitabine in patients with suppressed HIV-1 infection. Accuracy (defined as the mean difference between eGFR and mGFR) and precision (defined as standard deviation (SD) of the mean difference between eGFR and mGFR) of the eGFRs were calculated using linear regression and Bland & Altman analysis. RESULTS: We included 19 patients, 18 men, 15 Caucasian, mean (SD) age 46.0 y (± 8.9) and BMI 23.9 kg/m2 (± 3.0). Mean (SD) mGFR was 102 ml/min/1.73 m2 (± 19), 4 patients had mild renal dysfunction. All eGFRs tended to underestimate true GFR, with best accuracy for C&G (-1 ml/min/1.73 m2), CKD-EPI (-1 ml/min/1.73 m2), 24 hcreatinine clearance (-2 ml/min/1.73 m2) and MDRD-6 (0 ml/min/1.73 m2), and worst for cystatin C-based (-9 ml/min/1.73 m2) and MDRD-4 estimations (-10 ml/min/1.73 m2). Accuracy worsened at higher mGFR, but was not significantly influenced by age. C&G tended to overestimate at higher BMI. Precision was comparable for all GFR estimations. CONCLUSIONS: In this limited number of patients with preserved renal function and suppressed HIV-infection C&G and CKD-EPI appeared to be the best reflection of real GFR and most practical tool for monitoring GFR.

Persistent decline in estimated but not measured glomerular filtration rate on tenofovir may reflect tubular rather than glomerular toxicity.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) has been associated with proximal renal tubulopathy and reduction in estimated glomerular filtration rate (eGFR), without accounting for the tubular secretion of creatinine. METHODS: A substudy was performed among 19 participants of a randomized 48-week trial, comparing continuing first-line zidovudine/lamivudine (ZDV/3TC) with switching to TDF/emtricitabine (FTC). GFR was measured with [(125)I]-iothalamate (mGFR) and effective renal plasma flow (ERPF) with [(131)I]-hippuran. eGFR and tubular effects were assessed using plasma and urine samples. RESULTS: Of the 19 patients, 18 were men, 15 whites, mean (SD) age 46.0 (8.9) years, plasma HIV-1 RNA less than 50 copies/ml in all. After 48 weeks, eGFR using Cockcroft-Gault equation and ERPF, but not mGFR, had significantly decreased, and urinary α1-microglobulin/creatinine and microalbumin/creatinine significantly increased in patients on TDF. Although phosphate metabolism on TDF was affected at week 4, differences between groups disappeared during follow-up. CONCLUSION: Replacing ZDV/3TC with TDF/FTC in this limited sample of virologically suppressed HIV-1-infected adults was associated with mild persistent tubular but not glomerular dysfunction over 48 weeks. The observed persistent decrease in Cockcroft-Gault-based eGFR, but not mGFR, rather than being indicative of glomerular dysfunction may be explained by TDF inhibiting tubular creatinine excretion.

High prevalence of reduced bone mineral density in primary HIV-1-infected men.

OBJECTIVE: To assess the bone mineral density (BMD) in a cohort of men with primary HIV-1 infection (PHI). METHODS: Thirty-three men with PHI had a dual-energy X-ray absorptiometry (DXA) of the lumbar spine, femoral neck and total hip. Osteopenia and osteoporosis were defined according to WHO criteria as T-scores between -1 and -2.5 and -2.5 or less, respectively. The association between clinical and laboratory parameters and BMD was investigated using multivariable linear regression analysis. RESULTS: Mean age was 38 (SD 9) years and mean body mass index (BMI) 22.7 (SD 3.3) kg/m. Twenty-four men (73%) had a negative or indeterminate Western blot, 32 men (97%) were combination antiretroviral therapy-naive. Mean plasma HIV-1 RNA was 5.0 (SD 1.2) log10 copies/ml. Mean lumbar spine T (-0.8, SD 1.3, P = 0.001) and Z-scores (-0.7, SD 1.3, P = 0.004) and femoral neck T-score (-0.5, SD 0.9, P = 0.003) were significantly lower compared to the reference population. 15/33 men (45%) had osteopenia and 2/33 (6%) osteoporosis. Markers of bone turnover did not differ between patients with or without osteopenia/osteoporosis. Age was negatively associated with femoral neck (beta-coefficient = -0.05, P < 0.001) and total hip T-scores (beta = -0.03, P = 0.04). BMI was associated with lumbar spine (beta = 0.3), femoral neck (beta = 0.2) and total hip (beta = 0.2) T-scores (P < 0.001) and thyroid-stimulating hormone (TSH) with lumbar spine (beta = 0.5, P = 0.045) and femoral neck T-scores (beta = 0.4, P = 0.005). Increased plasma viral load was associated with lower total hip T-scores (beta = -0.2, P = 0.02). CONCLUSIONS: Reduced BMD was prevalent in PHI men and was associated with increased age, lower BMI and TSH levels, and higher levels of HIV-1 viremia.

Efavirenz: a review.

Efavirenz is a non-nucleoside reverse transcriptase inhibitor that in most treatment guidelines is recommended to be taken combined with two nucleoside analogue reverse transcriptase inhibitors, as a preferred first-line regimen for the treatment of HIV-1 infection. The antiretroviral efficacy of efavirenz-based combination regimens is good, as has been demonstrated in many clinical trials. Efavirenz has a long plasma half-life, which allows for once-daily dosing, but, as a consequence of this and the low genetic barrier, it is also prone to select for viral resistance when adherence to therapy is suboptimal. The most frequently encountered side effects are neuropsychiatric symptoms. These side effects are usually transient, but have been shown to persist for up to 2 years after initiation of therapy in some patients. This review outlines important and recent pharmacological and clinical data, which explain why efavirenz became a component of preferred treatment regimens today.

Hyperlactataemia in HIV-infected patients: the role of NRTI-treatment.

BACKGROUND: Long-term treatment with nucleoside reverse transcriptase inhibitors (NRTIs) can induce mitochondrial dysfunction, most severely represented by lactic acidosis. Diagnostic tests for mitochondrial dysfunction are lacking, although persistently elevated serum lactate might be a surrogate marker. OBJECTIVES: To determine the occurrence of hyperlactataemia in HIV-infected patients on NRTI-treatment and to evaluate the possible risk factors. METHODS: Cross-sectional analysis of lactic-acid levels in asymptomatic HIV-infected patients. Hyperlactactaemia was considered mild if between 2.0-5 mmol/l, serious if >5 mmol/l and lactic acidosis was defined as lactic acid levels >5 mmol/l with bicarbonate <20 mmol/l. Possible risk factors, such as current and preceding NRTI-treatment as well as treatment with non-nucleoside reverse transcriptase inhibitors or protease inhibitors and concurrent liver disease, were analysed. RESULTS: Two hundred and twenty three asymptomatic HIV-infected patients were studied, including 174 patients (78%) on NRTI treatment, 12 patients (5%) treated without NRTIs and 37 patients (17%) not treated. Mild hyperlactataemia was found in 42 patients (19%), from whom 38/42 (90%) were NRTI-treated and the remaining patients (4/42, 10%) received no treatment (chi2, P<0.05). The significant risk factors for hyperlactataemia in the univariate analysis were NRTI-treatment as a group (P=0.03) and elevated ALT (P=0.008). In multivariate analysis NRTI use (P=0.05) and ALT level (P=0.03) remained a significant determinant of hyperlactataemia. Among the different individual NRTIs, a stavudine-containing (P=0.004) and a zalcitabine-containing (P=0.07) regimen were most notably associated with the development of hyperlactataemia, whereas for the combinations of NRTIs, such association was only found for stavudine/lamivudine (P=0.05). CONCLUSIONS: A correlation between hyperlactataemia and NRTI treatment was found, but the value of routine lactate measurement for individual treatment monitoring remains uncertain.