ritonavir and Substance-Related-Disorders

AbbVie's 3 direct-acting antiviral (3D) regimen containing ombitasvir, paritaprevir, ritonavir, and dasabuvir with and without ribavirin is approved for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection. Safe and efficacious antiviral regimens resulting in minimal to no drug-drug interactions (DDIs) with antiretrovirals are needed to ensure that patients coinfected with HCV and the human immunodeficiency virus (HIV) achieve 12-week sustained virologic response rates similar to HCV-monoinfected patients. Also, the prevalence of injection drug use history is high in both monoinfected and HIV/HCV-coinfected patients. This review summarizes results from phase 1 DDI studies of the 3D regimen and antiretrovirals or drugs to treat substance abuse. Data suggest the 3D regimen is a viable option for HIV/HCV-coinfected patients on antiretroviral therapy containing tenofovir/emtricitabine, abacavir/lamivudine, dolutegravir, raltegravir, or atazanavir. HCV-infected patients receiving medications for substance abuse, particularly methadone or buprenorphine/naloxone, can also be treated with the 3D regimen.

Topics: 2-Naphthylamine; Anilides; Anti-Retroviral Agents; Carbamates; Coinfection; Cyclopropanes; Drug Interactions; Drug Therapy, Combination; Hepatitis C; HIV Infections; Humans; Lactams, Macrocyclic; Macrocyclic Compounds; Proline; Protease Inhibitors; Ritonavir; Substance-Related Disorders; Sulfonamides; Uracil; Valine

Multidrug regimens and corresponding drug interactions cause many adverse reactions and treatment failures. Drug efflux transporters: P-gp, MRP, BCRP in conjunction with metabolizing enzymes (CYPs) are major factors in such interactions. Most effective combination antiretrovirals (ARV) therapy includes a PI or a NNRTI or two NRTI. Coadministration of such ARV may induce efflux transporters and/or CYP3A4 resulting in sub-therapeutic blood levels and therapeutic failure due to reduced absorption and/or increased metabolism. A similar prognosis is true for ARV-compounds and drugs of abuse combinations. Morphine and nicotine enhance CYP3A4 and MDR1 expression in vitro. A 2.5 fold rise of cortisol metabolite was evident in smokers relative to nonsmokers. Altered functions of efflux transporters and CYPs in response to ARV and drugs of abuse may result in altered drug absorption and metabolism. Appropriate in vitro models can be employed to predict such interactions. Influence of genetic polymorphism, SNP and inter-individual variation in drug response has been discussed. Complexity underlying the relationship between efflux transporters and CYP makes it difficult to predict the outcome of HAART as such, particularly when HIV patients taking drugs of abuse do not adhere to HAART regimens. HIV(+) pregnant women on HAART medications, indulging in drugs of abuse, may develop higher viral load due to such interactions and lead to increase in mother to child transmission of HIV. A multidisciplinary approach with clear understanding of mechanism of interactions may allow proper selection of regimens so that desired therapeutic outcome of HAART can be reached without any side effects.

Topics: Analgesics, Opioid; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Benzodiazepines; Cocaine; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Female; HIV Infections; Humans; Methamphetamine; Neoplasm Proteins; Pregnancy; Ritonavir; Substance-Related Disorders

This study assessed the clinical efficacy of nirmatrelvir plus ritonavir (NMV-r) in treating patients with coronavirus disease-2019 (COVID-19) and substance use disorders (SUDs). This study included two cohorts: the first examined patients with SUDs, with and without a prescription for NMV-r, while the second compared patients prescribed with NMV-r, with and without a diagnosis of SUDs. SUDs were defined using ICD-10 codes, related to SUDs, including alcohol, cannabis, cocaine, opioid, and tobacco use disorders (TUD). Patients with underlying SUDs and COVID-19 were identified using the TriNetX network. We used 1:1 propensity score matching to create balanced groups. The primary outcome of interest was the composite outcome of all-cause hospitalization or death within 30 days. Propensity score matching yielded two matched groups of 10 601 patients each. The results showed that the use of NMV-r was associated with a lower risk of hospitalization or death, 30 days after COVID-19 diagnosis (hazard ratio (HR), 0.640; 95% confidence interval (CI): 0.543-0.754), as well as a lower risk of all-cause hospitalization (HR, 0.699; 95% CI: 0.592-0.826) and all-cause death (HR, 0.084; 95% CI: 0.026-0.273). However, patients with SUDs had a higher risk of hospitalized or death within 30 days of COVID-19 diagnosis than those without SUDs, even with the use of NMV-r (HR, 1.783; 95% CI: 1.399-2.271). The study also found that patients with SUDs had a higher prevalence of comorbidities and adverse socioeconomic determinants of health than those without SUDs. Subgroup analysis showed that the benefits of NMV-r were consistent across most subgroups with different characteristics, including age (patients aged ≥60 years [HR, 0.507; 95% CI: 0.402-0.640]), sex (women [HR, 0.636; 95% CI: 0.517-0.783] and men [HR, 0.480; 95% CI: 0.373-0.618]), vaccine status (vaccinated <2 doses [HR, 0.514; 95% CI: 0.435-0.608]), SUD subtypes (alcohol use disorder [HR, 0.711; 95% CI: 0.511- 0.988], TUD [HR, 0.666; 95% CI: 0.555-0.800]) and Omicron wave (HR, 0.624; 95% CI: 0.536-0.726). Our findings indicate that NMV-r could reduce all-cause hospitalization and death in the treatment of COVID-19 among patients with SUDs and support the use of NMV-r for treating patients with SUDs and COVID-19.

Topics: COVID-19; COVID-19 Drug Treatment; COVID-19 Testing; Female; Humans; Male; Ritonavir; Substance-Related Disorders; Treatment Outcome

Chemsex has been reported among men who have sex with men (MSM) living with HIV. There have been concerns about potentially harmful drug-drug interactions between chemsex drugs and antiretroviral therapy (ritonavir and cobicistat). We aimed to describe the prevalence and patterns of chemsex users in our HIV clinic population and to evaluate antiretroviral prescribing among chemsex users.. We undertook a cross-sectional study of patients attending our HIV clinic between January 2019 and December 2020. We collected data on patients who disclosed recent recreational drug use including chemsex in the previous 3 months.. In all, 2202/2501 (88%) patients were asked about recreational drug use and 514 (23%) disclosed recreational drug use. Eighty-two (4%) of these disclosed recent chemsex; 73 (89%) used crystal methamphetamine, 51 (62%) used gamma-hydroxybutyrate (GHB)/gamma-butyrolactone (GBL), 55 (67%) reported poly-drug use and 63 (76%) reported injecting drug use. The chemsex users were all cis-male MSM and were significantly older (53 vs. 46 years, p < 0.0001), and more likely to have had previous syphilis (73% vs. 28%, p < 0.0001) than patients reporting non-chemsex drug use. All chemsex users were prescribed antiretrovirals and 74 (90%) had an undetectable HIV viral load; 31 (38%) patients were taking either ritonavir (N = 12) or cobicistat (N = 19) as part of their antiretroviral regimen and this was similar to other patients attending for HIV care [31/82 (38%) vs. 768/2419 (31%), p = 0.25].. The prevalence of chemsex users among our HIV clinic attendants is 4%, and 38% of these were prescribed either ritonavir or cobicistat. Chemsex use should be a factor in antiretroviral therapy decision-making to avoid potential harm.

Topics: Anti-Retroviral Agents; Cobicistat; Cross-Sectional Studies; HIV Infections; Homosexuality, Male; Humans; Illicit Drugs; Male; Ritonavir; Sexual and Gender Minorities; Sexual Behavior; Substance-Related Disorders; United Kingdom; Unsafe Sex

Hyperbilirubinemia is a common finding in individuals with a history of substance abuse. Although this may indicate a serious disorder of liver function, this is not always the case. An understanding of bilirubin formation, metabolism, and transport can provide a helpful approach to dealing with these patients. This is typified by studies of patients treated with the antiretroviral drug atazanavir. Atazanavir has been associated with hyperbilirubinemia in as many as one-third of individuals for whom it has been prescribed, evoking concerns of hepatotoxicity. The studies in this report were designed to determine mechanisms by which this occurs. The data show that this drug inhibits the enzyme UDP-glucuronosyl transferase-1A1, responsible for conjugating bilirubin with glucuronic acid. This conjugation step is required for bilirubin excretion into bile, and when it is inhibited, bilirubin refluxes from the liver into the circulation, causing unconjugated hyperbilirubinemia. Other parameters of bilirubin formation, binding to albumin in the circulation, uptake into hepatocytes, and intracellular protein binding in hepatocytes were unaffected by atazanavir. The effect of atazanavir on serum bilirubin levels is reversible, consistent with lack of structural damage to the liver.

Topics: Animals; Atazanavir Sulfate; Bilirubin; Cells, Cultured; Female; Glucuronosyltransferase; Glutathione Transferase; Hepatocytes; HIV Protease Inhibitors; Humans; Hyperbilirubinemia; Male; Rats, Wistar; Ritonavir; Substance-Related Disorders

The main objective is to evaluate the efficacy and durability of lopinavir-ritonavir monotherapy (LPV/r-MT) in virologically controlled HIV-positive individuals switching from combination antiretroviral therapy (cART).. Criteria to be included in this observational study were to have initiated for the first time LPV/r-MT after ≥2 consecutive HIV RNA≤50 copies/ml achieved on a ≥3-drug-including regimen. The main end points were time to virological rebound (VR; defined in two ways: time of first of two consecutive viral load [VL]>50 and >200 copies/ml), time to discontinuation/intensification and time to experience either a single VL>200 copies/ml or discontinuation/intensification (treatment failure [TF]). Individuals' follow-up accrued from the date of starting LPV/r-MT to event or last available VL. Kaplan-Meier curves and Cox regression analyses were used.. A total of 228 individuals were included: median age 46 years (IQR 40-50), 36% females, 36% intravenous drug users and 25% HCV-coinfected. Median CD4(+) T-cell count at nadir was 215 cell/mm(3) (IQR 116-336) and at baseline was 615 cell/mm(3) (IQR 436-768). By 36 months after switching to LPV/r-MT, the proportion of individuals with VR (confirmed VL>200 copies/ml) was 11% and with TF was 35%. In the multivariable Cox model the factors associated with a lower risk of TF was the duration of viral suppression <50 copies/ml prior to baseline (ARH=0.92; 95% CI 0.85, 0.99; P=0.024, per 6 months longer) and having LPV/r as part of last cART (ARH=0.45; 95% CI 0.21, 0.95; P=0.037).. In daily clinical practice, we confirm a relatively safe approach of treatment simplification to LPV-MT in a selected population with long-lasting virological control.

Topics: Adult; Anti-HIV Agents; Drug Therapy, Combination; Female; Hepacivirus; Hepatitis C; HIV Infections; HIV-1; Humans; Lopinavir; Male; Middle Aged; Prospective Studies; Ritonavir; RNA, Viral; Substance-Related Disorders; Time Factors; Viral Load

We report three cases of tricuspid valve infective endocarditis associated with intravenous nyoape use. Nyoape is a variable drug combination of an antiretroviral (efavirenz or ritonavir), heroin, metamphetamines and cannabis. Its use is becoming increasingly common among poor communities in South Africa. All our patients were young HIV-positive men from disadvantaged backgrounds. They all presented with tricuspid regurgitation and septic pulmonary emboli. They were treated with prolonged intravenous antibiotic courses, and one required referral for surgery.

Topics: Adult; Alkynes; Anti-Bacterial Agents; Benzoxazines; Cannabis; Cyclopropanes; Endocarditis; Heroin; HIV Infections; Humans; Illicit Drugs; Male; Methamphetamine; Pulmonary Embolism; Ritonavir; South Africa; Substance-Related Disorders; Tricuspid Valve; Tricuspid Valve Insufficiency; Young Adult

Opioid addiction and HIV disease frequently co-occur. Adverse drug interactions have been reported between methadone and some HIV medications, but less is known about interactions between buprenorphine, an opioid partial agonist used to treat opioid dependence, and HIV therapeutics. This study examined drug interactions between buprenorphine and the protease inhibitors atazanavir and atazanavir/ritonavir. Opioid-dependent, buprenorphine/naloxone-maintained, HIV-negative volunteers (n=10 per protease inhibitor) participated in two 24-h sessions to determine pharmacokinetics of (1) buprenorphine and (2) buprenorphine and atazanavir (400mg daily) or atazanavir/ritonavir (300/100mg daily) following administration for 5 days. Objective opiate withdrawal scale scores and mini-mental state examination were determined prior to and following antiretroviral administration to examine pharmacodynamic effects. Pharmacokinetics of atazanavir and atazanavir/ritonavir were compared in subjects and matched, healthy controls (n=10 per protease inhibitor) to determine effects of buprenorphine. With atazanavir and atazanavir/ritonavir, respectively concentrations of buprenorphine (p<0.001, p<0.001), norbuprenorphine (p=0.026, p=0.006), buprenorphine glucuronide (p=0.002, p<0.001), and norbuprenorphine glucuronide (NS, p=0.037) increased. Buprenorphine treatment did not significantly alter atazanavir or ritonavir concentrations. Three buprenorphine/naloxone-maintained participants reported increased sedation with atazanavir/ritonavir. Atazanavir or atazanavir/ritonavir may increase buprenorphine and buprenorphine metabolite concentrations and might require a decreased buprenorphine dose.

Topics: Adult; Analgesics, Opioid; Atazanavir Sulfate; Buprenorphine; Drug Interactions; Female; HIV Infections; HIV Protease Inhibitors; Humans; Male; Middle Aged; Oligopeptides; Pyridines; Ritonavir; Substance-Related Disorders

Combination antiretroviral therapy including protease inhibitors such as ritonavir has added significant potency to therapy for human immunodeficiency viral (HIV) infection as well as substantial drug-drug interactions. Methadone metabolism is affected by cytochrome P450 (CYP) 3A4 inhibitors or inducers. Because ritonavir can induce CYP3A, it can decrease methadone plasma levels. An HIV-infected patient receiving methadone maintenance experienced withdrawal symptoms after ritonavir, saquinavir, and stavudine were added to his regimen; the most likely cause was ritonavir.

Topics: Analgesics, Opioid; Anti-HIV Agents; Diagnosis, Differential; Drug Interactions; Drug Therapy, Combination; HIV Infections; HIV Protease Inhibitors; Humans; Male; Methadone; Middle Aged; Ritonavir; Saquinavir; Stavudine; Substance Withdrawal Syndrome; Substance-Related Disorders