Clinical practice guideline for the management of chronic kidney disease in patients infected with HIV: 2014 update by the HIV Medicine Association of the Infectious Diseases Society of America.

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.

A review of the toxicity of HIV medications.

Antiretroviral therapy has changed human immunodeficiency virus (HIV) infection from a near-certainly fatal illness to one that can be managed chronically. More patients are taking antiretroviral drugs (ARVs) for longer periods of time, which naturally results in more observed toxicity. Overdose with ARVs is not commonly reported. The most serious overdose outcomes have been reported in neonates who were inadvertently administered supratherapeutic doses of HIV prophylaxis medications. Typical ARV regimens include a "backbone" of two nucleoside reverse transcriptase inhibitors (NRTI) and a "base" of either a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor. New classes of drugs called entry inhibitors and integrase inhibitors have also emerged. Older NRTIs were associated with mitochondrial toxicity, but this is less common in the newer drugs, emtricitabine, lamivudine, and tenofovir. Mitochondrial toxicity results from NRTI inhibition of a mitochondrial DNA polymerase. Mitochondrial toxicity manifests as myopathy, neuropathy, hepatic failure, and lactic acidosis. Routine lactate assessment in asymptomatic patients is not indicated. Lactate concentration should be obtained in patients taking NRTIs who have fatigue, nausea, vomiting, or vague abdominal pain. Mitochondrial toxicity can be fatal and is treated by supportive care and discontinuing NRTIs. Metabolic cofactors like thiamine, carnitine, and riboflavin may be helpful in managing mitochondrial toxicity. Lipodystrophy describes changes in fat distribution and lipid metabolism that have been attributed to both PIs and NRTIs. Lipodystrophy consists of loss of fat around the face (lipoatrophy), increase in truncal fat, and hypertriglyceridemia. There is no specific treatment of lipodystrophy. Clinicians should be able to recognize effects of chronic toxicity of ARVs, especially mitochondrial toxicity.

Antiretroviral treatment strategies in highly treatment experienced perinatally HIV-infected youth.

BACKGROUND: There is limited information on antiretroviral (ARV) regimens and outcomes in perinatally HIV (PHIV)-infected youth. Substantial drug resistance after long-term ARV use and nonadherence hinder efforts to design suppressive regimens for PHIV-infected youth. This study compares clinical outcomes by expected activity of the prescribed ARV regimens. METHODS: A retrospective cohort study of 13- to 24-year-old PHIV-infected youth on stable ARV regimens for ≥6 months was conducted at a pediatric HIV clinic. ARV regimens were retrospectively categorized as optimal or suboptimal based on accumulated genotypic resistance before study regimen initiation. RESULTS: Fifty-two patients with similar baseline characteristics met inclusion criteria (21 optimal and 31 suboptimal regimens). Patients receiving optimal regimens had significantly higher increases in CD4 than those given suboptimal regimens by week 48 of treatment (+62 versus +8 cells/mm, respectively; P = 0.04) and by the end of study period (+93 versus -1 cells/mm, respectively; P = 0.03). There were no significant differences between the groups in decline of viral load, frequency of opportunistic infections or hospitalizations or accumulation of resistance mutations. Overall, 60% of the optimal and 45% of the suboptimal groups had nonadherence during the study regimen (P = 0.3). CONCLUSIONS: PHIV-infected youth receiving optimal regimens had greater CD4 improvements but no difference in virologic outcomes compared with those receiving suboptimal regimens. In a patient population with significant nonadherence, providers must weigh the immunologic benefits of initiating an optimal regimen versus the potential risks of further resistance accumulation limiting future treatment options.

Antiretroviral therapy adherence and drug-drug interactions in the aging HIV population.

It is estimated that by 2015 more than half of all HIV-infected individuals in the United States will be 50 years of age or older. As this population ages, the frequency of non-AIDS related comorbidities increases, which includes cardiovascular, metabolic, gastrointestinal, genitourinary and psychiatric disorders. As a result, medical management of the aging HIV population can be complicated by polypharmacy and higher pill burden, leading to poorer antiretroviral therapy (ART) adherence. Adherence to ART is generally better in older populations when compared to younger populations; however, cognitive impairment in elderly patients can impair adherence, leading to worse treatment outcomes. Practical monitoring tools can improve adherence and increase rates of viral load suppression. Several antiretroviral drugs exhibit inhibitory and/or inducing effects on cytochrome P450 isoenzymes, which are responsible for the metabolism of many medications used for the treatment of comorbidities in the aging HIV population. The combination of ART with polypharmacy significantly increases the chance of potentially serious drug-drug interactions (DDIs), which can lead to drug toxicity, poorer ART adherence, loss of efficacy of the coadministered medication, or virologic breakthrough. Increasing clinicians awareness of common DDIs and the use of DDI programs can prevent coadministration of potentially harmful combinations in elderly HIV-infected individuals. Well designed ART adherence interventions and DDI studies are needed in the elderly HIV population.

Antiretroviral medication errors remain high but are quickly corrected among hospitalized HIV-infected adults.

BACKGROUND: Antiretroviral therapy (ART) medication errors can lead to drug resistance, treatment failure, and death. Prior research suggests that ART medication errors are on the rise in US hospitals. This analysis provides a current estimate of inpatient antiretroviral prescribing errors. METHODS: Retrospective review of medication orders during the first 48 hours of hospitalization for patients with human immunodeficiency virus (HIV) infection admitted to the Johns Hopkins Hospital between 1 January and 31 December 2009. Errors were classified as (1) incomplete regimen, (2) incorrect dosage, (3) incorrect schedule, and (4) nonrecommended drug-drug combinations. Multivariable regression was used to identify factors associated with errors. RESULTS: A total of 702 admissions occurred in 2009. Of these, 380 had ART medications prescribed on the first day and 308 on the second day of hospitalization. A total of 145 ART medication errors in 110 admissions were identified on the first day (29%), and 22 errors were identified in 21 admissions on the second day (7%). The most common errors were incomplete regimen and incorrect dosage or schedule. Protease inhibitors accounted for the majority of dosing and scheduling errors (71%-73%). Compared with patients admitted to the HIV/AIDS service, those admitted to surgical services were at increased risk of errors (adjusted odds ratio, 3.10; 95% confidence interval, 1.18-8.18). CONCLUSIONS: ART medication errors are common among hospitalized HIV-infected patients on the first day of admission, but most are corrected within 48 hours. Interventions are needed to safeguard patients and prevent serious complications of ART medication errors especially during the first 24 hours of hospitalization.

Severe prolonged sedation associated with coadministration of protease inhibitors and intravenous midazolam during bronchoscopy.

STUDY OBJECTIVE: To determine whether human immunodeficiency virus (HIV)-positive patients who received intravenous midazolam during an inpatient bronchoscopy procedure were more likely to experience severe prolonged sedation if they were taking antiretroviral therapy that included a protease inhibitor versus those who were not taking any antiretroviral therapy. DESIGN: Retrospective cohort study. SETTING: Tertiary care academic medical center. PATIENTS: Two hundred forty-one HIV-positive adults who received intravenous midazolam while undergoing bronchoscopy between January 1, 2003, and December 31, 2006, were analyzed; 51 patients were taking an antiretroviral regimen that included a protease inhibitor (exposed group), whereas 190 patients were not taking any antiretroviral agents (nonexposed group). MEASUREMENTS AND MAIN RESULTS: Patient demographics, medication administration records, and bronchoscopy data were collected from electronic databases and patient medical records. The exposed and nonexposed groups had similar demographic characteristics except that patients in the exposed group had lower HIV viral loads and were less likely to have altered mental status or respiratory distress before bronchoscopy. In addition, the exposed group had a higher proportion of males and patients with hepatitis B or C virus coinfection. The incidence of severe prolonged sedation was 9.80% in the exposed group versus 1.58% in the nonexposed group (relative risk [RR] 6.21, 95% confidence interval [CI] 1.53-25.12). Specific protease inhibitors associated with severe prolonged sedation were atazanavir-ritonavir and lopinavir-ritonavir. Length of hospital stay was approximately 3 days longer in the exposed group compared with the nonexposed group. CONCLUSION: Although the interaction between intravenous midazolam and protease inhibitors is well known, this study was the first systematic evaluation, to our knowledge, of the risk of severe prolonged sedation in a cohort of hospitalized HIV-positive patients. Coadministration of protease inhibitors with intravenous midazolam was associated with severe prolonged sedation as well as increased length of hospital stay. Therefore, concomitant use of these drugs should be closely monitored, or alternative sedatives for procedural sedation should be considered.

Provisional guidance on the use of hepatitis C virus protease inhibitors for treatment of hepatitis C in HIV-infected persons.

In May 2011, hepatitis C virus (HCV) protease inhibitors (PIs) were approved by the US Food and Drug Administration to treat persons with genotype 1 chronic hepatitis C virus (HCV) infection, but not those dually infected with human immunodeficiency virus (HIV). Although critical safety and efficacy data are lacking, the availability of the drugs and substantial medical need justify the off-label use of HCV PIs in select HIV/HCV-coinfected persons. Pending results of ongoing investigations, this article represents provisional guidance on the use of HCV PIs in HIV-infected persons.

Emerging antiretroviral drug interactions.

With HIV-infected patients living longer and recommendations to initiate antiretrovirals (ARVs) being made earlier, the likelihood for potential drug-drug interactions between ARVs and concurrent medications used to manage co-morbid conditions will increase. In order to maximize the clinical benefit and minimize potential toxicity of ARVs and co-administered medications, it is important for clinicians to recognize significant drug-drug interactions. This article highlights clinically significant drug-drug interactions with antituberculosis agents, antimalarials, anticoagulants, chemotherapeutic agents and pulmonary antihypertensive agents when they are co-administered with newer ARVs (e.g. darunavir, raltegravir, maraviroc and etravirine).

Twice-daily versus once-daily antiretroviral therapy and coformulation strategies in HIV-infected adults: benefits, risks, or burden?

The recent development of once-daily antiretroviral agents and fixed-dose combination formulations has been an important development in antiretroviral regimen simplification. Recent studies indicate that once-daily antiretroviral regimens improve adherence, especially in antiretroviral-naïve patients and in difficult-to-treat populations, such as the homeless or marginally housed. However, there are potential risks with the higher peak and lower trough plasma drug concentrations that may result from certain once-daily formulations. Due to the multifactorial and complex nature of adherence behavior, clinicians' efforts to improve patient adherence should not be limited to prescribing once-daily regimens, but should also consider social support, side effect management, and adherence support tools, such as pillbox organizers and other targeted interventions. Additional research will clarify the benefits of once-daily and fixed-dose combination regimens on clinical and virologic outcomes. Comprehensive cost-benefit analysis of regimen simplification could help facilitate evidence-based decisions regarding antiretroviral regimen choices.

Tenofovir disoproxil fumarate in the treatment of chronic hepatitis B.

Tenofovir is a nucleotide analog reverse transcriptase inhibitor approved recently by the US FDA for the treatment of chronic hepatitis B (CHB) in adult patients based on the results of two double-blind randomized trials demonstrating superiority of tenofovir compared with adefovir. Tenofovir is available orally as tenofovir disoproxil fumarate (ester pro-drug of tenofovir) and inhibits replication of both hepatitis B virus and HIV-1. Owing to its potent antiviral activity, favorable safety profile, and higher barrier to the development of resistance, tenofovir has replaced adefovir as a first-line oral monotherapy option in the treatment of CHB in the 2009 update of the American Association for the Study of Liver Diseases (AASLD) Practice Guidelines. Additionally, tenofovir monotherapy or in combination with nucleoside analogs are options for patients who have developed resistance to other CHB therapies including lamivudine and adefovir.

HIV infection-related tuberculosis: clinical manifestations and treatment.

Several aspects of human immunodeficiency virus (HIV) infection-related tuberculosis (TB) and its treatment differ from those of TB in HIV-uninfected persons. The risk of TB and the clinical and radiographic manifestations of disease are primary examples. Antiretroviral therapy has a profound effect on lowering the risk of TB in HIV-infected persons, but it can also be associated with immune reconstitution inflammatory disease and unmasking of previously subclinical disease. There are also differences in treatment of HIV infection-related TB because of overlapping drug toxicities and drug-drug interactions between antiretroviral therapy and anti-TB therapy.

Antiretroviral adherence and pharmacokinetics: review of their roles in sustained virologic suppression.

High levels of adherence to antiretrovirals are important to prevent the development of genotypic resistance and achieve virologic suppression. Although the decreased complexity of regimens is associated with improved adherence, there is little evidence that adherence is better with once-daily dosing regimens compared to twice-daily regimens. The relationship between adherence, resistance, and virologic suppression is different for different classes of antiretrovirals. Boosted protease inhibitor (PI)-based regimens are preferred to unboosted PI-based regimens for patients with poor adherence. With PI-based regimens, the pharmacologic consequence of a single missed dose is greater with a once-daily regimen than with a twice-daily regimen (e.g., once-daily versus twice-daily lopinavir/ritonavir). Although resistance is a concern for patients taking non-nucleoside reverse transcriptase inhibitor-based regimens with imperfect adherence, virologic suppression can be achieved with less than 95% adherence. It is important for clinicians to address adherence problems in their patients and to tailor individual regimens based on treatment history, genotype resistance, side effect profile, drug interactions, pharmacokinetics, schedule preferences, and perceived adherence.

Tenofovir for the treatment of hepatitis B virus.

Tenofovir disoproxil fumarate is a nucleotide analog reverse transcriptase inhibitor recently approved by the United States Food and Drug Administration (FDA) for the treatment of chronic hepatitis B virus (HBV) infection in adults. Tenofovir has been available in the United States for the treatment of human immunodeficiency virus (HIV) since 2001. It blocks HBV replication in liver cells and is available as a once-daily oral formulation. The efficacy of tenofovir for the treatment of chronic HBV has been demonstrated to be superior to adefovir in randomized controlled trials, which led to its FDA approval for use in chronic HBV. Because of its potent antiviral activity, favorable safety profile, and higher barrier to the development of resistance, tenofovir should replace adefovir as a first-line monotherapy option in the treatment of HBV in monoinfected patients. In the HIV-HBV-coinfected population, tenofovir is already a preferred agent in combination with other anti-HBV agents (lamivudine or emtricitabine), which are cotreatments for HIV as well. In addition, tenofovir monotherapy or in combination with nucleoside analogs are options for patients who have developed resistance to other therapies for chronic HBV, including lamivudine and adefovir.

Amprenavir and lopinavir pharmacokinetics following coadministration of amprenavir or fosamprenavir with lopinavir/ritonavir, with or without efavirenz.

BACKGROUND: Amprenavir (APV), fosamprenavir (FPV), lopinavir (LPV), ritonavir (RTV) and efavirenz (EFV) are to varying degrees substrates, inducers and inhibitors of CYP3A4. Coadministration of these drugs might result in complex pharmacokinetic drug-drug interactions. METHODS: Two prospective, open-label, non-randomized studies evaluated APV and LPV steady-state pharmacokinetics in HIV-infected patients on APV 750 mg twice daily + LPV/RTV 533/133 mg twice daily with EFV (n=7) or without EFV (n=12) + background nucleosides (Study 1) and after switching FPV 1,400 mg twice daily for APV (n=10) (Study 2). RESULTS: In Study 1 EFV and non-EFV groups did not differ in APV minimum plasma concentration (Cmin; 1.10 versus 1.06 microg/ml, P = 0.89), area under the concentration-time curve (AUC; 17.46 versus 24.34 microg x h/ml, P = 0.22) or maximum concentration (Cmax; 2.61 versus 4.33 microg/ml, P = 0.08); for LPV there was no difference in Cmin, (median: 3.66 versus 6.18 microg/ml, P = 0.20), AUC (81.84 versus 93.75 microg x h/ml, P = 0.37) or Cmax (10.36 versus 10.93 microg/ml, P = 0.61). In Study 2, after switching from APV to FPV, APV Cmin increased by 58% (0.83 versus 1.30 microg/ml, P = 0.0001), AUC by 76% (19.41 versus 34.24 micorg x h/ml, P = 0.0001), and Cmax by 75% (3.50 versus 6.14, P = 0.001). Compared with historical controls, LPV and RTV pharmacokinetics were not changed. All treatment regimens were well tolerated. Seven of eight completers (88%) maintained HIV-1 RNA <400 copies/ml 12 weeks after the switch (1 lost to follow up). CONCLUSIONS: EFV did not appear to significantly alter APV and LPV pharmacokinetic parameters in HIV-infected patients taking APV 750 mg twice daily + LPV 533/133 mg twice daily. Switching FPV 1400 mg twice daily for APV 750 mg twice daily resulted in an increase in APV Cmin, AUC, and Cmax without changing LPV or RTV pharmacokinetics or overall tolerability.

Beneficial pharmacokinetic interaction between atazanavir and lopinavir/ritonavir.

BACKGROUND: The combination of lopinavir/ritonavir (LPV/r) and atazanavir (ATV) with nucleoside reverse transcriptase inhibitors has been used as a salvage regimen in HIV-infected patients. Because these agents, to various degrees, are substrates, inducers, and inhibitors of CYP450 3A4, there is concern for alterations in the pharmacokinetics (PK) of these combined agents. OBJECTIVE: To determine the steady-state PK interactions between ATV, ritonavir (RTV), and LPV when coadministered at various doses. METHODS: HIV-negative subjects (n = 15) received a combination of ATV, RTV, and LPV in the following sequence: period I (days 1-10), ATV/r at a dose of 300/100 mg once daily; period II (days 11-24), ATV at a dose of 300 mg once daily plus LPV/r at a dose of 400/100 mg twice daily; and period III (days 25-34), ATV/r at a dose of 300/100 mg once daily plus LPV/r at a dose of 400/100 mg twice daily. Intensive PK analysis was performed on days 10, 24, and 34. A paired t test was used for pairwise comparison of log-transformed PK parameters of ATV and LPV. RESULTS: In period II, the ATV minimum concentration (Cmin) geometric mean (GM) was higher compared with period I (GM: 0.75 vs. 0.51 microg/mL, geometric mean ratio (GMR) = 1.45, 90% confidence interval [CI]: 1.19 to 1.77; P = 0.006). The ATV area under the concentration-time curve from dosing to 24 hours after the dose (AUC0-24; GM: 36.40 vs. 39.62 microg.h/mL, GMR = 0.92, 90% CI: 0.80 to 1.05; P = 0.28) did not differ, however. The addition of 100 mg of RTV in period III did not significantly increase the ATV Cmin (GM: 0.84 vs. 0.75 microg/mL, GMR = 1.13, 90% CI: 0.91 to 1.40; P = 0.34) or ATV AUC0-24 (GM: 39.59 vs. 36.40 microg.h/mL, GMR = 1.09, 90% CI: 0.99 to 1.20; P = 0.14) compared with period II. The additional RTV in period III resulted in a higher LPV Cmin (GM: 5.12 vs. 3.99 microg/mL, GMR = 1.28, 90% CI: 1.15 to 1.43; P = 0.001), but the LPV areas under the concentration-time curve from dosing to 12 hours after the dose and maximum concentration were not significantly different. LPV PK parameters in period II were comparable to those of historical control subjects receiving LPV/r at a dose of 400/100 mg twice daily. All studied regimens were well tolerated. Indirect hyperbilirubinemia was the only grade 3 and 4 abnormality reported, which was expected given that ATV competitively inhibits UGTIA1 and has not been shown to result in other hepatic abnormalities. CONCLUSIONS: The combination of ATV at a dose of 300 mg once daily plus LPV/r at a dose of 400/100 mg twice daily resulted in an appropriate PK profile for ATV and LPV and could be further evaluated in treatment-experienced patients requiring a dual-boosted protease inhibitor-containing regimen.