Tony Antoniou

Interactions between Recreational Drugs and Antiretroviral Agents

OBJECTIVE: To summarize existing data regarding potential interactions between recreational drugs and drugs commonly used in the management of HIV-positive patients. DATA SOURCES: Information was obtained via a MEDLINE search (1966–August 2002) using the MeSH headings human immunodeficiency virus, drug interactions, cytochrome P450, medication names commonly prescribed for the management of HIV and related opportunistic infections, and names of commonly used recreational drugs. Abstracts of national and international conferences, review articles, textbooks, and references of all articles were also reviewed. STUDY SELECTION AND DATA EXTRACTION: Literature on pharmacokinetic interactions was considered for inclusion. Pertinent information was selected and summarized for discussion. In the absence of specific data, prediction of potential clinically significant interactions was based on pharmacokinetic and pharmacodynamic properties. RESULTS: All protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors are substrates and potent inhibitors or inducers of the cytochrome P450 system. Many classes of recreational drugs, including benzodiazepines, amphetamines, and opioids, are also metabolized by the liver and can potentially interact with antiretrovirals. Controlled interaction studies are often not available, but clinically significant interactions have been observed in a number of case reports. Overdoses secondary to interactions between the “rave” drugs methylenedioxymethamphetamine (MDMA) or γ-hydroxybutyrate (GHB) and PIs have been reported. PIs, particularly ritonavir, may also inhibit metabolism of amphetamines, ketamine, lysergic acid diethylmide (LSD), and phencyclidine (PCP). Case series and pharmacokinetic studies suggest that nevirapine and efavirenz induce methadone metabolism, which may lead to symptoms of opiate withdrawal. A similar interaction may exist between methadone and the PIs ritonavir and nelfinavir, although the data are less consistent. Opiate metabolism can be inhibited or induced by concomitant PIs, and patients should be monitored for signs of toxicity and/or loss of analgesia. PIs should not be coadministered with midazolam and triazolam, since prolonged sedation may occur. CONCLUSIONS: Interactions between agents commonly prescribed for patients with HIV and recreational drugs can occur, and may be associated with serious clinical consequences. Clinicians should encourage open dialog with their patients on this topic, to avoid compromising antiretroviral efficacy and increasing the risk of drug toxicity.

Systematic Review of HIV Transmission between Heterosexual Serodiscordant Couples where the HIV-Positive Partner Is Fully Suppressed on Antiretroviral Therapy

Background The risk of sexual HIV transmission in serodiscordant couples when the HIV-positive partner has full virologic suppression on combination antiretroviral therapy (cART) is debated. This study aims to systematically review observational studies and randomized controlled trials (RCTs), evaluating rates of sexual HIV transmission between heterosexual serodiscordant couples when the HIV-positive partner has full suppression on cART. Methods and Findings We searched major bibliographic databases to November 2012 for relevant observational studies and RCTs without language restrictions. Conference proceedings, key journals and bibliographies were also searched. Studies reporting HIV transmission rates, cART histories and viral loads of the HIV-positive partners were included. Two reviewers extracted methodologic characteristics and outcomes. Of 20,252 citations, 3 studies met all eligibility criteria with confirmed full virologic suppression in the HIV-positive partner. We included 3 additional studies (2 cohort studies, 1 RCT) that did not confirm viral suppression in the HIV-positive partner at transmission in a secondary meta-analysis. Methodologic quality was reasonable. The rate of transmission in the 3 studies confirming virologic suppression was 0 per 100 person-years (95% CI = 0–0.05), with low heterogeneity (I2 = 0%). When we included the 3 studies that did not confirm virologic suppression, the rate of transmission was 0.14 per 100 person-years (95%CI = 0.04–0.31) (I2 = 0%). In a sensitivity analysis including all 6 studies, the rate of transmission was 0 per 100 person-years (95%CI = 0–0.01) after omitting all transmissions with known detectable or unconfirmed viral loads, as full suppression in these cases was unlikely. Limitations included lack of data on same-sex couples, type of sexual intercourse (vaginal vs. anal), direction of HIV transmission, exact viral load at the time of transmission, sexually transmitted infections (STI) rates, and extent of condom use. Conclusions Our findings suggest minimal risk of sexual HIV transmission for heterosexual serodiscordant couples when the HIV-positive partner has full viral suppression on cART with caveats regarding information on sexual intercourse type, STIs, and condom use. These findings have implications when counseling heterosexual serodiscordant couples on sexual and reproductive health. More research is needed to explore HIV transmission risk between same-sex couples.

Interactions Between Antiretrovirals and Antineoplastic Drug Therapy

Despite the established impact of highly active antiretroviral therapy (HAART) in reducing HIV-related morbidity and mortality, malignancy remains an important cause of death. Patients who receive the combination of cancer chemotherapy and HAART may achieve better response rates and higher rates of survival than patients who receive antineoplastic therapy alone. However, the likelihood of drug interactions with combined therapy is high, since protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) are substrates and potent inhibitors or inducers of the cytochrome P450 (CYP) system. Since many antineoplastic drugs are also metabolised by the CYP system, coadministration with HAART could result in either drug accumulation and possible toxicity, or decreased efficacy of one or both classes of drugs. Although formal, prospective pharmacokinetic interaction studies are not available in most instances, it is possible to infer the nature of drug interactions based on the metabolic fates of these agents.Paclitaxel and docetaxel are both metabolised by the CYP system, although differences exist in the nature of the isoenzymes involved. Case reports describing adverse consequences of concomitant taxane-antiretroviral therapy exist. Although other confounding factors may have been present, these cases serve as reminders of the vigilant monitoring necessary when taxanes and HAART are coadministered. Similarly, vinca alkaloids are substrates of CYP3A4 and are, thus, vulnerable to PI- or NNRTI-mediated changes in their pharmacokinetics. Interactions with the alkylating agents cyclophosphamide and ifosfamide are complicated as a result of the involvement of the CYP3A4 and CYP2B6 isoenzymes in both the metabolic activation of these drugs and the generation of potentially neurotoxic metabolites. Existing data regarding the metabolic fate of the anthracyclines doxorubicin and daunorubicin suggest that clinically detrimental interactions would not be expected with coadministered HAART. Commonly used endocrine therapies are largely substrates of the CYP system and may, therefore, be amenable to modulation by concomitant HAART. In addition, tamoxifen itself has been associated with reduced concentrations of both anastrozole and letrozole, raising the concern that similar inducing properties may adversely affect the outcome of PI- or NNRTI-based therapy. Similarly, dexamethasone is both a substrate and concentration-dependent inducer of CYP3A4; enhanced corticosteroid pharmacodynamics may result with CYP3A4 inhibitors, while the efficacy of concomitant HAART may be compromised with prolonged dexamethasone coadministration. Since PIs and NNRTIs may also induce or inhibit the expression of P-glycoprotein, the potential for additional interactions to arise via modulation of this transporter also exists. Further research delineating the combined safety and pharmacokinetics of antiretrovirals and antineoplastic therapy is necessary.

Incidence of and risk factors for tenofovir‐induced nephrotoxicity: a retrospective cohort study

Despite the recent publication of case reports describing various manifestations of tenofovir‐related nephrotoxicity, data regarding the incidence of and risk factors for this adverse effect are currently lacking.

Trimethoprim-Sulfamethoxazole-Induced Hyperkalemia in Patients Receiving Inhibitors of the Renin-Angiotensin System A Population-Based Study

BACKGROUND Trimethoprim therapy can cause hyperkalemia and is often coprescribed with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs). The objective of this study was to characterize the risk of hyperkalemia-associated hospitalization in elderly patients who were being treated with trimethoprim-sulfamethoxazole along with either an ACEI or an ARB. METHODS We conducted a population-based, nested case-control study of a cohort of elderly patients 66 years or older who were residents of Ontario, Canada, and who were receiving continuous therapy with either an ACEI or an ARB. Case patients were those with a hyperkalemia-associated hospitalization within 14 days of receiving a prescription for trimethoprim-sulfamethoxazole, amoxicillin, ciprofloxacin, norfloxacin, or nitrofurantoin. For each case, we identified up to 4 control patients from the same cohort matched for age, sex, and presence or absence of chronic renal disease and diabetes. Odds ratios were determined for the association between hyperkalemia-associated hospitalization and previous antibiotic use. RESULTS During the 14-year study period, we identified 4148 admissions involving hyperkalemia, 371 of which occurred within 14 days of antibiotic exposure. Compared with amoxicillin, the use of trimethoprim-sulfamethoxazole was associated with a nearly 7-fold increased risk of hyperkalemia-associated hospitalization (adjusted odds ratio, 6.7; 95% confidence interval, 4.5-10.0). No such risk was found with the use of comparator antibiotics. CONCLUSIONS Among older patients treated with ACEIs or ARBs, the use of trimethoprim-sulfamethoxazole is associated with a major increase in the risk of hyperkalemia-associated hospitalization relative to other antibiotics. Alternate antibiotic therapy should be considered in these patients when clinically appropriate.

Validation of Case-Finding Algorithms Derived from Administrative Data for Identifying Adults Living with Human Immunodeficiency Virus Infection

Objective We sought to validate a case-finding algorithm for human immunodeficiency virus (HIV) infection using administrative health databases in Ontario, Canada. Methods We constructed 48 case-finding algorithms using combinations of physician billing claims, hospital and emergency room separations and prescription drug claims. We determined the test characteristics of each algorithm over various time frames for identifying HIV infection, using data abstracted from the charts of 2,040 randomly selected patients receiving care at two medical practices in Toronto, Ontario as the reference standard. Results With the exception of algorithms using only a single physician claim, the specificity of all algorithms exceeded 99%. An algorithm consisting of three physician claims over a three year period had a sensitivity and specificity of 96.2% (95% CI 95.2%–97.9%) and 99.6% (95% CI 99.1%–99.8%), respectively. Application of the algorithm to the province of Ontario identified 12,179 HIV-infected patients in care for the period spanning April 1, 2007 to March 31, 2009. Conclusions Case-finding algorithms generated from administrative data can accurately identify adults living with HIV. A relatively simple “3 claims in 3 years” definition can be used for assembling a population-based cohort and facilitating future research examining trends in health service use and outcomes among HIV-infected adults in Ontario.

Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study

Objective To determine whether the prescription of co-trimoxazole with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker is associated with sudden death. Design Population based nested case-control study. Setting Ontario, Canada, from 1 April 1994 to 1 January 2012. Participants Ontario residents aged 66 years or older treated with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker. Cases were those who died suddenly shortly after receiving an outpatient prescription for one of co-trimoxazole, amoxicillin, ciprofloxacin, norfloxacin, or nitrofurantoin. Each case was matched with up to four controls on age, sex, chronic kidney disease, and diabetes. Main outcome measure Odds ratio for the association between sudden death and exposure to each antibiotic relative to amoxicillin, after adjustment for predictors of sudden death according to a disease risk index. Results Of 39 879 sudden deaths, 1027 occurred within seven days of exposure to an antibiotic and were matched to 3733 controls. Relative to amoxicillin, co-trimoxazole was associated with an increased risk of sudden death (adjusted odds ratio 1.38, 95% confidence interval 1.09 to 1.76). The risk was marginally higher at 14 days (adjusted odds ratio 1.54, 1.29 to 1.84). This corresponds to approximately three sudden deaths within 14 days per 1000 co-trimoxazole prescriptions. Ciprofloxacin (a known cause of QT interval prolongation) was also associated with an increased risk of sudden death (adjusted odds ratio 1.29, 1.03 to 1.62), but no such risk was observed with nitrofurantoin or norfloxacin. Conclusions In older patients receiving angiotensin converting enzyme inhibitors or angiotensin receptor blockers, co-trimoxazole is associated with an increased risk of sudden death. Unrecognized severe hyperkalemia may underlie this finding. When appropriate, alternative antibiotics should be considered in such patients.

Immediate versus delayed polyalkylimide gel injections to correct facial lipoatrophy in HIV-positive patients

Objective:To evaluate the safety and efficacy of polyalkylimide gel (PAIG) in the treatment of HIV-associated facial lipoatrophy. Design:A randomized, open-label, single-centre study. Methods:HIV-positive individuals with facial lipoatrophy (based on physician assessment) were randomly assigned to immediate (weeks 0 and 6) or delayed (weeks 12 and 18) PAIG injections administered into the subcutaneous plane. Outcome measures included a change in facial lipoatrophy severity scores (five-point scale), adverse events, photographic assessment, and changes in quality of life (QoL), depression and anxiety using validated surveys. Results:Thirty-one patients (median age 48 years, 97% male) were enrolled and completed 48 weeks of follow-up. Overall, the median volume of product injected bilaterally was 16.0 ml. Adverse events, including swelling, redness, bruising and pain, were mild, and resolved after a median of 3 days. There were no cases of necrosis, nodules or infection. Compared with patients randomly assigned to delayed treatment, patients in the immediate therapy group had significantly lower physician-rated facial lipoatrophy scores (0 versus 2; P < 0.0001), improved QoL (P = 0.01), and lower anxiety (P = 0.02) at week 12. At week 48, median physician and patient facial lipoatrophy scores were 0 and 1, respectively, for the entire cohort, and were not significantly different between the groups. Significant improvements in patient anxiety (P = 0.001) and depression (P = 0.01) were observed from baseline to week 48. Conclusion:Treatment with PAIG was effective and safe and led to improvements in facial lipoatrophy grading, QoL, anxiety and depression scores in HIV-infected patients with facial lipoatrophy.

Tenofovir: A Nucleotide Analog for The Management of Human Immunodeficiency Virus Infection

Tenofovir disoproxil fumarate, an acyclic nucleotide analog of adenosine monophosphate, is the most recent addition to the antiretroviral arsenal. After conversion to tenofovir by diester hydrolysis, subsequent phosphorylation by cellular enzymes to form the active tenofovir diphosphate is necessary for antiretroviral activity. Preliminary data suggest that tenofovir is as safe and efficacious as stavudine when given in combination with lamivudine and efavirenz for the treatment of antiretroviral‐naïve patients. In antiretroviral‐experienced patients, the addition of tenofovir to stable background antiretroviral therapy resulted in approximately a 0.6 log10 copies/ml reduction in viral load relative to placebo. Extended follow‐up suggests that such virologic gains may be durable. In vitro, recombinant human immunodeficiency virus (HIV) expressing the K65R mutation showed a 3–4‐fold increase in the 50% inhibitory concentrations of tenofovir when compared with wild type. In vivo, this mutation thus far appears to occur infrequently and is associated with variable virologic responses. Response rates to tenofovir vary with the number and pattern of thymidine analog mutations present before starting treatment with this agent. Tenofovir appears to be a well‐tolerated agent in patients who are heavily pretreated and who have advanced disease. The main adverse effects appear to be gastrointestinal in nature and include nausea, vomiting, and diarrhea. In animals, osteomalacia and nephrotoxicity have occurred with tenofovir at exposures much higher than those observed in humans. Although no patient had to discontinue therapy as a result of elevated creatinine levels or hypophosphatemia through 58 weeks of treatment, the toxicities associated with long‐term tenofovir therapy in humans are unknown. Concomitant administration of tenofovir and didanosine increases the area under the concentration‐time curve of the latter by 44–60%; monitoring for signs and symptoms of didanosine toxicity is recommended. The approved dosage of tenofovir is 300 mg (one tablet) once/day with meals. Given the ease of administration and relative safety from the perspectives of adverse effects and drug interactions, tenofovir has the potential to assume a large role in the treatment of patients with HIV infection.

Trimethoprim-sulfamethoxazole induced hyperkalaemia in elderly patients receiving spironolactone: nested case-control study

Objectives To characterise the risk of admission to hospital for hyperkalaemia in elderly patients treated with trimethoprim-sulfamethoxazole in combination with spironolactone. Design Population based nested case-control study. Setting Ontario, Canada, from 1 April 1992 to 1 March 2010. Participants Cases were residents of Ontario aged 66 years or above receiving chronic treatment with spironolactone and admitted to hospital with hyperkalaemia within 14 days of receiving a prescription for either trimethoprim-sulfamethoxazole, amoxicillin, norfloxacin, or nitrofurantoin. Up to four controls for each case were identified from the same cohort, matched on age, sex, and presence or absence of chronic kidney disease and diabetes, and required to have received one of the study antibiotics within 14 days before the case’s index date. Main outcome measures Odds ratio for association between admission to hospital with hyperkalaemia and receipt of a study antibiotic in the preceding 14 days, adjusted for conditions and drugs that may influence risk of hyperkalaemia. Results During the 18 year study period, 6903 admissions for hyperkalaemia were identified, 306 of which occurred within 14 days of antibiotic use. Of these, 248 (81%) cases were matched to 783 controls. 10.8% (17 859/165 754) of spironolactone users received at least one prescription for trimethoprim-sulfamethoxazole. Compared with amoxicillin, prescription of trimethoprim-sulfamethoxazole was associated with a marked increase in the risk of admission to hospital for hyperkalaemia (adjusted odds ratio 12.4, 95% confidence interval 7.1 to 21.6). The population attributable fraction was 59.7%, suggesting that approximately 60% of all cases of hyperkalaemia in older patients taking spironolactone and treated with an antibiotic for a urinary tract infection could be avoided if trimethoprim-sulfamethoxazole was not prescribed. Treatment with nitrofurantoin was also associated with an increase in the risk of hyperkalaemia (adjusted odds ratio 2.4, 1.3 to 4.6), but no such risk was found with norfloxacin (adjusted odds ratio 1.6, 0.8 to 3.4) Conclusions Among older patients receiving spironolactone, treatment with trimethoprim-sulfamethoxazole was associated with a major increase in the risk of admission to hospital for hyperkalaemia. This drug combination should be avoided when possible.