David M. Burger

Antiretroviral treatment of adult HIV infection: 2014 recommendations of the International Antiviral Society-USA Panel.

CONTEXT Recent data regarding the consequences of untreated human immunodeficiency virus (HIV) infection and the expansion of treatment choices for antiretroviral-naive and antiretroviral-experienced patients warrant an update of the International AIDS Society-USA guidelines for the use of antiretroviral therapy in adults with HIV infection. OBJECTIVES To provide updated recommendations for management of HIV-infected adults, using antiretroviral drugs and laboratory monitoring tools available in the international, developed-world setting. This report provides guidelines for when to initiate antiretroviral therapy, selection of appropriate initial regimens, patient monitoring, when to change therapy, and what regimens to use when changing. DATA SOURCES AND STUDY SELECTION A panel with expertise in HIV research and clinical care reviewed relevant data published or presented at selected scientific conferences since the last panel report through April 2010. Data were identified through a PubMed search, review of scientific conference abstracts, and requests to antiretroviral drug manufacturers for updated clinical trials and adverse event data. DATA EXTRACTION AND SYNTHESIS New evidence was reviewed by the panel. Recommendations were drafted by section writing committees and reviewed and edited by the entire panel. The quality and strength of the evidence were rated and recommendations were made by full panel consensus. CONCLUSIONS Patient readiness for treatment should be confirmed before initiation of antiretroviral treatment. Therapy is recommended for asymptomatic patients with a CD4 cell count < or = 500/microL, for all symptomatic patients, and those with specific conditions and comorbidities. Therapy should be considered for asymptomatic patients with CD4 cell count > 500/microL. Components of the initial and subsequent regimens must be individualized, particularly in the context of concurrent conditions. Patients receiving antiretroviral treatment should be monitored regularly; treatment failure should be detected and managed early, with the goal of therapy, even in heavily pretreated patients, being HIV-1 RNA suppression below commercially available assay quantification limits.

Adverse effects of reverse transcriptase inhibitors: mitochondrial toxicity as common pathway

After zidovudine (ZDV), a 3′-azido analogue of thymi-dine, was found to be an effective antiretroviral drugagainst HIV [1,2], other nucleoside analogues inhibit-ing reverse transcriptase (RT) soon followed: didano-sine (ddI), zalcitabine (ddC), lamivudine (3TC),stavudine (D4T), and recently abacavir (1592U89)[3–7]. These drugs have demonstrated efficacy inreduction of morbidity and mortality, especially incombination therapy [8–10]. A special feature of someof these drugs is the protection against AIDS dementiacomplex, which appears to be related to good penetra-tion of the blood–brain barrier [11–13]. Although theintroduction of protease inhibitors has changed themanagement of HIV infection drastically, this cerebro-protective property will assert the role of these nucleo-side RT inhibitors (NRTI) as a cornerstone ofantiretroviral therapy [9,10].More than 10 years of experience with NRTI therapyhas revealed important adverse effects ranging frommild (myopathy) to fatal in some cases (pancreatitis,liver failure and lactic acidosis). Behind most of theseside-effects there appears to be a common mechanism:a decreased mitochondrial energy-generating capacity.In this review we will summarize the literature inwhich this mechanism is analysed and will emphasizethe importance of acquired mitochondrial dysfunctionthat will accumulate during long-term treatment withantiretroviral nucleoside analogues.

Prospective randomized two-arm controlled study to determine the efficacy of a specific intervention to improve long-term adherence to highly active antiretroviral therapy.

Background: Nearly perfect compliance seems to be indispensable to obtain the maximum benefit from highly active antiretroviral therapy (HAART). Interventions to ensure a high level of adherence during a relatively long‐term period of therapy are necessary. Methods: This is a prospective, randomized, two‐arm controlled study including patients starting their first‐ or second‐line HAART who were randomized to receive psychoeducative intervention to implement adherence (experimental group [EG]) or a usual medical follow‐up (control group [CG]). We aimed to study the efficacy of a psychoeducative intervention to ensure long‐term adherence to HAART, its relation with the virologic efficacy of treatment, and to determine the variables related to long‐term adherence. Visits were made at weeks 0, 4, 24, and 48 for data collection. Self‐reported adherence was registered at each visit and its veracity was tested by randomized blood analyses performed without previous warning to 40% of patients. Appropriate adherence was defined as the consumption of ≥95% of medication prescribed. Statistical analyses were performed both by the as treated (AT) and the intention to treat missing = failure (ITT) methods. Results: In all, 116 patients were included. At week 48, 94% of patients in the EG versus 69% controls achieved adherence ≥95% (p = .008); 89% of patients in the EG versus 66% controls had HIV‐1 RNA levels <400 copies/ml (p = .026). Overall, 85% of patients with adherence ≥95% but only 45% of those with adherence <95% had viral load (VL) <400 copies/ml (p = .008). In multivariate analysis, variables significantly related to adherence were having received a psychoeducative intervention (odds ratio [OR], 6.58; p = .04), poor effort to take medication (OR, 5.38; p = .03), and high self‐perceived capacity to follow the regimen (OR, 13.76; p = .04). Self‐reported adherence and drug plasma levels coincided in 93% of cases. However, differences in adherence did not reach statistical significance in the ITT analysis although a clear tendency toward benefit was observed in EG. Conclusions: Specific and maintained psychoeducative interventions based on excellence on clinical practice are useful to keep high levels of adherence as well as high levels of viral suppression. There is a clear relation between high adherence levels and virologic success. Assessment of certain specific variables related to adherence may be helpful to monitor patients compliance in the clinical setting.

Clinical Relevance of the Pharmacokinetic Interactions of Azole Antifungal Drugs with Other Coadministered Agents

There are currently a number of licensed azole antifungal drugs; however; only 4 (namely, fluconazole, itraconazole, posaconazole, and voriconazole) are used frequently in a clinical setting for prophylaxis or treatment of systemic fungal infections. In this article, we review the pharmacokinetic interactions of these azole antifungal drugs with other coadministered agents. We describe these (2-way) interactions and the extent to which metabolic pathways and/or other supposed mechanisms are involved in these interactions. This article provides an overview of all published drug-drug interactions in humans (either healthy volunteers or patients), and on the basis of these findings, we have developed recommendations for managing the specific interactions.

Vitamin D Deficiency among HIV Type 1-Infected Individuals in the Netherlands: Effects of Antiretroviral Therapy

Vitamin D regulates bone metabolism but has also immunoregulatory properties. In HIV-infected patients bone disorders are increasingly observed. Furthermore, low 1,25(OH)(2)D(3) levels have been associated with low CD4(+) counts, immunological hyperactivity, and AIDS progression rates. Few studies have examined the vitamin D status in HIV-infected patients. This study will specifically focus on the effects of antiretroviral agents on vitamin D status. Furthermore, the effect of vitamin D status on CD4 cell recovery after initiation of HAART will be evaluated. Among 252 included patients the prevalence of vitamin D deficiency (<35 nmol/liter from April to September and <25 nmol/liter from October to March) was 29%. Female sex, younger age, dark skin, and NNRTI treatment were significant risk factors in univariate analysis, although in multivariate analyses skin pigmentation remained the only independent risk factor. Median 25(OH)D(3) levels were significantly lower in white NNRTI-treated patients [54.5(27.9-73.8) nmol/liter] compared to white PI-treated patients [77.3 (46.6-100.0) nmol/liter, p = 0.007], while among nonwhites no difference was observed. Both PI- and NNRTI-treated patients had significantly higher blood PTH levels than patients without treatment. Moreover, NNRTI treatment puts patients at risk of elevated PTH levels (>6.5 pmol/liter). Linear regression analysis showed that vitamin D status did not affect CD4 cell recovery after initiation of HAART. In conclusion, 29% of the HIV-1-infected patients had vitamin D deficiency, with skin color as an independent risk factor. NNRTI treatment may add more risk for vitamin D deficiency. Both PI- and NNRTI-treated patients showed higher PTH levels and might therefore be at risk of bone problems. Evaluation of 25(OH)D(3) and PTH levels, especially in NNRTI-treated and dark skinned HIV-1-infected patients, is necessary to detect and treat vitamin D deficiency early.

Evaluation of antiretroviral therapy results in a resource-poor setting in Blantyre, Malawi

Objective  To evaluate treatment results of the paying antiretroviral therapy (ART) clinic of Queen Elizabeth Central Hospital, a large public and teaching hospital in Blantyre, Malawi. The only ART was a fixed drug combination of stavudine, lamivudine and nevirapine.

Long-term neuropsychiatric disorders on efavirenz-based approaches : Quality of life, psychologic issues, and adherence

Background:Efavirenz has been associated with neuropsychiatric disorders, although little is known about its long-term toxicity. Objective:To assess neuropsychiatric disorders and their relation to efavirenz plasma levels as well as quality of life, psychologic status, and adherence in HIV-infected patients on long-term efavirenz-based antiretroviral therapy. Methods:Cross-sectional study comparing 60 patients on an efavirenz-based approach (EFV group) and 60 patients on a protease inhibitor-containing regimen (PI group) for at least 1 year. Adverse events, efavirenz plasma levels, quality of life, psychologic status, and adherence were assessed. Results:The mean time on treatment was 91.1 ± 39.5 weeks in the EFV group and 119.9 ± 67.4 weeks in the PI group. Mild dizziness, sadness, mood changes, irritability, lightheadedness, nervousness, impaired concentration, abnormal dreams, and somnolence were reported more frequently in the EFV group than in the PI group (P < 0.05). Forty-nine of 60 patients presented with therapeutic efavirenz plasma levels (range: 1.0-4.0 mg/L). Efavirenz plasma levels were similar in subjects with and without neuropsychiatric disorders. No significant differences were found between the EFV group and the PI group regarding quality of life and psychologic status. Sixty percent of patients in the EFV group and 55% in the PI group reported adherence ≥95%. Conclusions:Mild and clinically tolerable neuropsychiatric disorders may persist in patients after a mean of 2 years using an efavirenz-based approach. Quality of life and psychologic status remained good in both study groups. Interventions to enhance long-term adherence should be applied in clinical practice.

Therapeutic drug monitoring: an aid to optimising response to antiretroviral drugs?

Therapeutic drug monitoring (TDM) has been proposed as a means to optimise response to highly active antiretroviral therapy (HAART) in HIV infection. Protease inhibitors (PIs) and the non-nucleoside reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine satisfy many criteria for TDM. Nucleoside reverse transcriptase inhibitors (NRTIs) are not suitable candidates for TDM, since no clear plasma concentration-effect relationships have been established for these drugs.Several important limitations to the application of TDM for antiretroviral drugs should be recognised, including uncertainty about the best pharmacokinetic predictor of response and insufficient validation of target concentrations for individual PIs and NNRTIs. Data from two clinical trials support the use of TDM in treatment-naive HIV-infected patients who start with an indinavir- or nelfinavir-based regimen. TDM either prevented virological failures (presumably by preventing the development of resistance) or treatment discontinuations due to concentration-related toxicity. Application of routine TDM in other patient groups (treatment-experienced patients) or for drugs other than indinavir or nelfinavir (NNRTIs, other PIs, combination of PIs) is speculative at this moment. However, TDM can be used in selected patient groups (children, pregnant women, patients with renal or hepatic dysfunction) to confirm adequate drug concentrations, and for management of drug-drug interactions.TDM in treatment-experienced patients may be optimally used in conjunction with resistance testing. The integration of pharmacological and virological measures in the inhibitory quotient (IQ) needs to be standardised and elaborated further. TDM should be accompanied by careful assessment of adherence and can itself help identify non-adherence, although a drug concentration only reflects the last few drug doses taken by a patient. Additional clinical trials are needed before routine TDM can be adopted as standard of care in the treatment of HIV infection.

Pharmacokinetics of Adjusted-Dose Lopinavir-Ritonavir Combined with Rifampin in Healthy Volunteers

ABSTRACT Coadministration of lopinavir-ritonavir, an antiretroviral protease inhibitor, at the standard dose (400/100 mg twice a day [BID]) with the antituberculous agent rifampin is contraindicated because of a significant pharmacokinetic interaction due to induction of cytochrome P450 3A by rifampin. In the present study, two adjusted-dose regimens of lopinavir-ritonavir were tested in combination with rifampin. Thirty-two healthy subjects participated in a randomized, two-arm, open-label, multiple-dose, within-subject controlled study. All subjects were treated with lopinavir-ritonavir at 400/100 mg BID from days 1 to 15. From days 16 to 24, the subjects in arm 1 received lopinavir-ritonavir at 800/200 mg BID in a dose titration, and the subjects in arm 2 received lopinavir-ritonavir at 400/400 mg BID in a dose titration. Rifampin was given at 600 mg once daily to all subjects from days 11 to 24. The multiple-dose pharmacokinetics of lopinavir, ritonavir, and rifampin were assessed. Twelve of 32 subjects withdrew from the study. For nine subjects lopinavir-ritonavir combined with rifampin resulted in liver enzyme level elevations. Pharmacokinetic data for 19 subjects were evaluable. Geometric mean ratios for the lopinavir minimum concentration in serum and the maximum concentration in serum (Cmax) on day 24 versus that on day 10 were 0.43 (90% confidence interval [CI], 0.19 to 0.96) and 1.02 (90% CI, 0.85 to 1.23), respectively, for arm 1 (n = 10) and 1.03 (90% CI, 0.68 to 1.56) and 0.93 (90% CI, 0.81 to 1.07), respectively, for arm 2 (n = 9). Ritonavir exposure increased from days 10 to 24 in both arms. The geometric mean Cmax of rifampin was 13.5 mg/liter (day 24) and was similar between the two arms. Adjusted-dose regimens of lopinavir-ritonavir in combination with therapeutic drug monitoring and monitoring of liver function may allow concomitant use of rifampin.

Simultaneous Determination of the Hiv Drugs Indinavir, Amprenavir, Saquinavir, Ritonavir, Lopinavir, Nelfinavir, the Nelfinavir Hydroxymetabolite M8, and Nevirapine in Human Plasma by Reversed-phase High-performance Liquid Chromatography

A reversed-phase high-performance liquid chromatography method for the simultaneous quantitative determination of the currently available HIV protease inhibitors amprenavir, indinavir, lopinavir, nelfinavir, ritonavir, saquinavir, the active nelfinavir metabolite M8, and the nonnucleoside reverse transcriptase inhibitor nevirapine in human plasma is described. The method involved liquid–liquid extraction from plasma, followed by high-performance liquid chromatography with an OmniSpher 5 C18 column and ultraviolet detection set at a wavelength of 215 nm for the protease inhibitors and 280 nm for nevirapine. The runtime was 25 minutes. The assay has been validated over the concentration range of 0.05 to 30 mg/L for indinavir, nelfinavir, ritonavir, and saquinavir, 0.07 to 30 mg/L for amprenavir and lopinavir, and 0.05 to 15 mg/L for M8 and nevirapine. This method proved to be simple, accurate, and precise and is useful for the therapeutic drug monitoring of protease inhibitors and the nonnucleoside reverse transcriptase inhibitor nevirapine on a routine basis.