Antiviral drugs

C H A P T E R

27 Antiviral drugs Eris Cani, BS, PharmD, BCPS*,1, Tae Eun Park, PharmD, BCPS, BCIDP†, Rebecca Kavanagh, PharmD, BCACP, AAHIVP* *Department of Pharmacy Practice, Touro College of Pharmacy, New York, NY, United States † BronxCare Health System, Bronx, NY, United States 1 Corresponding author: [email protected]

DRUGS ACTIVE AGAINST CYTOMEGALOVIRUS (CMV)

Foscarnet [SEDA-35, 504; SEDA-36, 403; SEDA-37, 329; SEDA-38, 262; SEDA-39, 270]

Ganciclovir and valganciclovir [SEDA-34, 449; SEDA-35, 504; SEDA-36, 404; SEDA-37, 330; SEDA-38, 262; SEDA-39, 270–271]

The most concerning adverse effects of foscarnet are renal failure and electrolyte imbalance, including hypocalcemia, hypophosphatemia, hypomagnesemia, and hypokalemia [5S]. Foscarnet is a nephrotoxic agent that causes acute tubular necrosis. Also, it produces complexes with divalent cations that have decreased solubility. Moreover, trisodium foscarnet chelates metallic ions, such as calcium, magnesium, iron, and zinc, leading to crystallization. Although kidney is the most common organ that is affected by precipitated crystals, other tissues, such as pulmonary parenchyma and esophageal and cardiac mucosa, can be involved as well [6E]. Even though foscarnet-induced renal impairment can occur at any time during the treatment, it usually emerges during the second week of induction therapy. Once serum creatinine (SCr) is increased, it may be reversible if foscarnet is discontinued early [5S].

The major concern of using ganciclovir and valganciclovir is myelosuppression, resulting in neutropenia and thrombocytopenia. Other adverse effects include anemia, fever, rash, headache, seizures, confusion, change in mental status, and gastrointestinal (GI) intolerance. It is recommended to avoid these agents in patients with severe neutropenia (absolute neutrophil count [ANC] <500 cells/ mm3), thrombocytopenia (<25000 cells/mm3), severe anemia (hemoglobin <8 g/dL), and renal failure. Neutropenia and anemia are reversible and respond to granulocytecolony stimulating factor and erythropoietin [1R,2R].

Cidofovir [SEDA-34, 447; SEDA-35, 503; SEDA-36, 401; SEDA-37, 329; SEDA-38, 261; SEDA-39, 269]

Letermovir [SEDA-38, 261; SEDA-39, 269]

The major adverse effect of cidofovir is nephrotoxicity, which is caused by rapid absorption of the drug into the proximal tubular cells by organic anion transporters (OAT), but slow secretion into the lumen. High intracellular concentration of cidofovir leads to tubular necrosis. In order to reduce the risk of nephrotoxicity from cidofovir, hydration prior to administering cidofovir with normal saline is essential. Also, probenecid 2 g 3 h before and 1 g 2 and 8 h after cidofovir infusion is recommended [3S]. Probenecid is an organic acid that competes with cidofovir for the OAT, which leads to lower intracellular concentration of cidofovir in tubular cells [4c].

In a phase 3, double-blind trial, the most common adverse effect of letermovir was acute graft-versus-host disease (GVHD) (38.5%), followed by diarrhea (24.5%) and nausea (23.4%). Acute kidney injury was reported in 9.7% and 13% of the letermovir and placebo groups, respectively. The major benefit of letermovir is that it does not cause myelosuppression, which was demonstrated by a meta-analysis of 12 trials that reported letermovir had reduced risk of adverse effects compared to ganciclovir [7C,8M]. Although it was not seen in clinical trials, transaminitis has been recently reported. A 42-year-old male was put on

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letermovir for secondary prophylaxis of CMV viremia approximately a year after hematopoietic stem cell transplant (HSCT). However, letermovir was held due to elevation of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin on day 3. Two days later, letermovir was restarted as the liver function tests were trending down, but they were stable for only a day, and AST and ALT began to rise again while total bilirubin remained stable. However, letermovir was continued at this time since the patient did not develop a grade 3 or higher transaminitis or clinical symptoms of hepatotoxicity. A probable causal relationship between letermovir and transaminitis was confirmed by Naranjo Scale [9A]. Maribavir A recent phase 2, randomized, dose-ranging, doubleblind study reported dysgeusia (65%) as the most common treatment-emergent adverse effect, which led to discontinuation of maribavir in one patient. Absolute neutrophil count of less than 1000 cells/mm3 was observed in 11% of the patients [10C].

are with intravenously administered acyclovir. Nevertheless, Chavez-Inguez and colleagues recently reported a 54-year-old female presenting with acute renal failure, hypokalemia, and biopsy-proven acute tubular necrosis and acute tubulointerstitital nephritis from oral acyclovir use [14A]. Another toxicity that can be observed, particularly in patients with baseline renal impairment, is neurotoxicity, which generally occurs 3 days after ingesting acyclovir. The exact mechanism of acyclovir causing neurotoxicity is unknown, though it can be attributed to the drug inhibiting deoxyribonucleic acid polymerase, leading to change in mitochondrial function [15A]. There are several cases reporting patients with chronic kidney disease or end-stage renal disease (ESRD) on dialysis presenting with altered mental status and visual hallucinations due to acyclovir-induced neurotoxicity [16A,17A,18A]. In most cases, neurotoxicity resolves in 2–7 days after discontinuing the drug and with supportive care [15A]. According to the available data, daily hemodialysis for extended period of time resolves acyclovir-induced neurotoxicity since acyclovir has a low volume of distribution and low protein binding [15A,17A,19A].

Brincidofovir [SEDA-39, 270] A randomized, double-blind, placebo-controlled, phase 3 trial showed that brincidofovir was more frequently associated with serious adverse events than placebo. The most common adverse event of brincidofovir was diarrhea (60.7%), followed by acute GVHD (57.1%), abdominal pain (34.3%), and nausea (30.7%) [11C]. Brincidofovir converts to cidofovir, which is the circulating metabolite. The peak cidofovir concentration after brincidofovir administration is less than 1% of that measured after intravenous cidofovir administration. Also, brincidofovir is not a substrate of OAT 1 unlike cidofovir. Therefore, brincidofovir has better safety profile on nephrotoxicity than cidofovir. According to the available clinical studies, more than 80% of the patients who switched from cidofovir or foscarnet to brincidofovir had improved renal function [12E].

DRUGS ACTIVE AGAINST HERPES VIRUSES (HSV) [SEDA-34, 450; SEDA-35, 507; SEDA-36, 407; SEDA-37, 332; SEDA-38, 263] Acyclovir [SEDA-39, 271–272] Acyclovir is generally well tolerated; however, nephrotoxicity has been widely reported. Deposition of crystals in renal tubules is the common mechanism of acyclovir-induced nephrotoxicity, although tubulopathy and acute tubular necrosis without crystallization have been reported as well [13S]. The most reported cases

Valacyclovir [SEDA-39, 271–272] Valacyclovir is a prodrug of acyclovir; therefore, it shares similar safety profile as acyclovir, including nephrotoxicity and neurotoxicity. One study reviewed the FDA Adverse Event Reporting System database and found that more patients develop acute kidney injury when a nonsteroidal anti-inflammatory drug (NSAID) is used with valacyclovir than with acyclovir. Also, the study demonstrated that certain NSAIDs, including loxoprofen, diclofenac, etodolac, ketorolac, piroxicam, and lornoxicam, are associated with increased risk of acute kidney injury when they are used concurrently with valacyclovir [20S,21c]. Similar to acyclovir, there are several reports of valacyclovir causing neurotoxicity, which is generally more often seen in patients with baseline renal impairment [22A,23A,24A,25A]. The common cause of neurotoxicity from valacyclovir in these cases was due to not adjusting the dose based on the renal function. The management of valacyclovir-induced neurotoxicity involved frequent or even daily, extended hemodialysis or peritoneal dialysis sessions to remove the drug [22A,23A,24A,25A,26A]. Interestingly, a case of an 88-year-old male with normal baseline renal function exhibiting altered mental status after taking valacyclovir for herpes zoster has been recently reported. He presented with acute kidney injury with blood and cerebrospinal fluid (CSF) acyclovir levels that were much higher than the therapeutic range of 0.4 and 2 μg/mL. The patient’s mental status improved with

DRUGS ACTIVE AGAINST HEPATITIS VIRUSES

intravenous hydration and valacyclovir withdrawal, the method the authors did not specify in the case report [15A]. Similar to the previous case, a 66-year-old female with normal renal function at baseline presented with altered mental status and slurred speech after starting valacyclovir for herpes zoster. She was in acute kidney injury with high levels of acyclovir in blood and CSF. After one session of hemofiltration, one session of hemoperfusion, and two sessions of hemodialysis, the patient regained her baseline altered mental status and renal function [27A].

Famciclovir [SEDA-39, 271–272] The most common adverse effects are headache, dizziness, and GI intolerance [28S]. Unlike acyclovir and valacyclovir, famciclovir has not been associated with renal failure, which has made it a good alternative agent for patients with baseline renal impairment. However, a pharmacokinetic study has demonstrated decreased renal clearance of famciclovir with worsening renal function [29R]. Therefore, it is crucial to adjust famciclovir dose based on the renal function [28S]. A recent multicenter, single-blind, active-controlled, parallel-group, noninferiority phase 3 trial demonstrated that the adverse effects occurred at a similar rate between famciclovir and acyclovir. The most commonly reported adverse effect was headache [30c].

DRUGS ACTIVE AGAINST HEPATITIS VIRUSES Interferon Pegylated interferon α-2a, once a mainstay for treatment of chronic hepatitis B and C, remains in limited use for patients with chronic hepatitis B infection [31S]. It has been phased out of first line therapy with the development of new agents that have superior efficacy and safety profiles. Interferon therapy is contraindicated in patients with advanced liver disease, portal hypertension, leukopenia, thrombocytopenia, severe depression or a history of major psychiatric illness, ongoing pregnancy, active autoimmune diseases, and severe concomitant diseases. Because of these restrictions and an extensive side effect profile, interferon therapy is usually limited to patients with only mild to moderate chronic hepatitis and reserved for patients who have a good chance of mounting a significant enough immune response to seroconvert from HBeAg to HBe antibody. These patients include those with low HBV viral load, high serum ALT levels, younger age, female sex, and no presence of fibrosis or cirrhosis. Peg-IFN is associated with numerous adverse effects in at least 30% of patients,

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some of which can be severe. The adverse effects most frequently observed include flu-like syndrome, headache, myalgia, fatigue, weight loss, depression, hair loss and local injection site reactions, neutropenia, and thrombocytopenia [32R].

Adefovir [SEDA-35, 507; SEDA-36, 409; SEDA-37, 333; SEDA-38, 264; SEDA-39, 272–273] Adefovir is considered an alternative treatment option for patients with chronic hepatitis B infection [31S]. A multicenter, prospective, open-label, randomizedcontrolled trial of renal function in 102 Chinese patients undergoing 48 weeks of therapy with PEG-IFN-α-2b and ADV vs PEG-IFN-α-2b alone investigated both efficacy and safety, namely, change in glomerular filtration rate (GFR). GFR was calculated using Cockcroft–Gault (CG), abbreviated Modification of Diet in Renal Disease (MDRD) study, and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. This study found a decrease in GFR for patients in both treatment groups. Patient age, HBV DNA level, and combined therapy (rather than monotherapy) were significant negative predictive factors for eGFR changes [33C]. These data are in contrast to previous literature has suggested that adefovir may be associated with nephrotoxicity.

Entecavir [SEDA-35, 512; SEDA-36, 411; SEDA-37, 335; SEDA-39, 273] Entecavir is a first-line treatment option for patients with chronic hepatitis B infection [31S]. Major adverse events associated with entecavir include pancreatitis, lactic acidosis, and renal function impairment [34c]. A prospective cohort study by Tonon et al. followed patients from 2008 to 2013 with chronic hepatitis B infection treated with tenofovir disoproxil fumarate (48 patients) or treated with entecavir (22 patients). No difference was found between the two groups in the plasmatic concentration of calcium, phosphate, vitamin D, parathyroid hormone, or creatinine. Furthermore, DEXA scan technology showed no difference in the T-score, and there was no significant difference in the Fracture Risk Assessment Tool estimate of 10-year risk of osteoporotic fractures in the two groups [35C].

Ribavirin [SEDA-35, 512; SEDA-36, 412; SEDA-37, 335; SEDA-38, 267; SEDA-39, 273] Hemolytic anemia With the advent of potent direct-acting antivirals, most patients with chronic hepatitis C virus (HCV) infection do not require ribavirin as part of their treatment regimen

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[36S]. In select cases, ribavirin may still be utilized by clinicians as alternative therapy or in patients with cirrhosis. Ribavirin is included in regimens treating non-cirrhotic hepatitis C genotype 1a in combination with paritaprevir, ritonavir, ombitasvir and dasabuvir; genotype 1a with resistance associated substitutions in combination with elbasvir/grazoprevir; genotype 3 with cirrhosis in combination with daclatasvir and sofosbuvir; and in genotype 4 in combination with paritaprevir, ombitasvir, and ritonavir. Ribavirin is suggested to induce hemolytic anemia, leading to increased serum bilirubin and decreased hemoglobin in clinical trials [37c,38C,39c,40c]. This anemia may be particularly apparent in patients with other risk factors for anemia. A study by Akhil et al. looking at safety and efficacy of sofosbuvir and ribavirin in Indian patients with hepatitis C and End Stage Renal Disease on hemodialysis found an incidence of ribavirin-associated anemia to be as high as 45% [41c]. A single-center study by Akin et al. conducted on 23 liver and/or renal transplant patients found that 3 patients (13%) developed anemia, 2 of whom were in the ledipasvir/sofosbuvir plus ribavirin group and 1 in the ledipasvir/sofosbuvir without ribavirin group, yielding a significantly higher risk of anemia development associated with ribavirin therapy (P ¼ 0.01) [42c].

DRUGS ACTIVE AGAINST HEPATITIS VIRUSES: COMBINATIONS Glecaprevir/pibrentasvir Glecaprevir/pibrentasvir is a first-line, pangenotypic option for patients with chronic HCV infection. Glecaprevir is used for 8 weeks in patients without cirrhosis or for 12 weeks in patients with cirrhosis [36S]. Glecaprevir/ pibrentasvir can be used in patients with poor renal function, including patients with end stage renal disease on hemodialysis. The ENDURANCE trials were phase 3b, single-arm, open-label, multicenter trials performed in adults with chronic HCV genotype 5 or 6 infection who were previously untreated or treatment-experienced. Five (6%) patients had serious adverse events, none of which were deemed related to glecaprevir/pibrentsavir or led to discontinuation. Fatigue and headache were the only adverse events that occurred in 10% or more of patients. This corroborates previous literature indicating that lecaprevir/pibrentasvir is overall well-tolerated by most patients [43C].

Sofosbuvir/velpatasvir Sofosbuvir/velpatasvir is a first-line, pangenotypic option for patients with chronic HCV infection. It is considered first line in patients with genotypes 1 through

6 and is used for 12 weeks regardless of the presence or absence of cirrhosis [36S]. This regimen is widely used due to its simple administration and mild adverse event profile. In a retrospective study of patients with compensated liver cirrhosis treated with sofosbuvir based hepatitis C regimens between January 2014 and December 2017 in a community clinic, Gayam et al. investigated treatment efficacy and adverse events in patients who received either ledipasvir/sofosbuvir (with or without ribavirin) or sofosbuvir/velpatasvir. Overall, efficacy after treatment was achieved in 90% in patients who received one of the two ribavirin-free regimens. In this study, fatigue, headache, rash, and thrombocytopenia were the most common adverse events observed in sofosbuvir-based regimens, and there were no serious adverse events in either LDV/ SOF or SOF/VEL [44c].

Ledipasvir/sofosbuvir Ledipasvir/sofosbuvir is a first-line regimen utilized regimen for patients with chronic hepatitis C infection and genotype 1, 4, 5, or 6 [36S]. This regimen, like other direct-acting antiviral combinations, is extremely well tolerated by most patients. Real-world data of ledipasvir/sofosbuvir were published by Aqel et al. in 37 patients with HCV genotype 1. These patients had relapsed post treatment with simeprevir plus sofosbuvir and were subsequently given LDV/SOF for 12 weeks [45c], and experienced minimal adverse effects. An open-label randomized study by Ahmed et al. on 200 treatment-naïve Egyptian patients with hepatitis C genotype 4 infection corroborated this low risk of adverse events. The most common side effects seen in this study included headache, fatigue, myalgia, and cough [36S].

Elbasvir/grazoprevir Elbasvir/grazoprevir is a first-line regimen for treatment of patients with chronic hepatitis C infection [36S]. It is used for patients with genotype 1 and 4. When used for genotype 1a, NS5A resistance testing is required prior to initial treatment. If no resistance associated substitutions are identified, elbasvir/grazoprevir is used for 12 weeks. If NS5A resistance associated substitutions are identified, treatment must be extended to 16 weeks, and ribavirin must be added to the regimen. A meta-analysis comparing use of elbasvir/grazoprevir vs elbasvir/grazoprevir with ribavirin pooled data from 8 randomized controlled trials (n ¼ 1297 patients). This study found significant incidence of headache, fatigue, ALT elevation, and AST elevation in the groups who received elbasvir/grazoprevir [46M].

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Sofosbuvir with simeprevir

Sofosbuvir with daclatasvir

Sofosbuvir with simeprevir is an alternative regimen used occasionally in patients with HCV genotype 1a and 1b without cirrhosis [36S]. In the United States, these antivirals are not co-formulated, necessitating two pills to be administered per day. Like other direct acting antivirals, simeprevir and sofosbuvir are well tolerated. Ahmed et al. conducted an open-label, multicenter, prospective study on 381 Egyptian patients. This study identified that common adverse effects of a SMV with SOF regimen included headache, fatigue, itching, photosensitivity, and cough [47c].

Sofosbuvir with daclatasvir is a relatively uncommon regimen for treatment of chronic hepatitis C. In the United States, these antivirals are not co-formulated, necessitating two pills to be administered per day. It is considered an alternative regimen for patients with HCV genotypes 1a or 1b without cirrhosis, or genotypes 2 or 3 with or without cirrhosis [36S]. When used for genotypes 2 or 3 with cirrhosis, sofosbuvir with daclatasvir must be administered for a longer duration of therapy, and ribavirin may be added. An observational cohort of 47 HCV-infected renal transplant recipients analyzed side effects seen in daclatasvir and non-daclatasvir-based regimens. Fourteen patients were treated with sofosbuvir and ribavirin for 24 weeks, 22 patients received sofosbuvir/ledipasvir and 12 patients received sofosbuvir and daclatasvir with (n ¼ 3) or without (n ¼ 31) ribavirin for 12 or 24 weeks. The only serious adverse effect was anemia observed in 8 (57%) patients in the sofosbuvir and ribavirin group. This indicates that sofosbuvir with daclatasvir was well tolerated, particularly when used without ribavirin [50c].

Paritaprevir/ritonavir/ombitasvir Paritaprevir, ritonavir, ombitasvir are occasionally utilized in treatment of chronic HCV genotype 4 in combination with ribavirin [36S]. A retrospective, multicenter study by Arai et al. evaluated 235 patients with chronic kidney disease and without CKD who were given paritaprevir, ritonavir, and ombitasvir for 12 weeks. There was no difference in the virologic response rates between the two groups. Furthermore, investigators found no significant differences in treatment emergent adverse events, nor in treatment discontinuation due to adverse events between the two groups [48c].

Paritaprevir/ritonavir/ombitasvir/dasabuvir Paritaprevir, ritonavir, ombitasvir with added dasabuvir are an alternative regimen occasionally used with ribavirin for chronic hepatitis C genotype 1a without cirrhosis, or for genotype 1b without ribavirin [36S]. A randomized, controlled, clinical trial by Solund et al. published data on adverse effects throughout their 24-week trial. They randomly assigned 96 patients in a 1:1 ratio, to treatment with either paritaprevir, ombitasvir, ritonavir, dasabuvir and RBV or LDV/SOF and RBV if HCV genotype 1 (72 patients) or to daclatasvir, sofosbuvir and RBV or SOF/RBV if HCV genotype 3 (24 patients). They found adverse events occurred in 70 (97%) patients with HCV genotype 1, and the most common adverse events were anemia (n ¼ 56, 78%), fatigue (n ¼ 53, 74%), and headache (n ¼ 33, 46%). In seven (11%) patients, adverse events assessed by the investigator to be related to the direct acting antiviral regimen were still present 12 weeks after treatment. There were no differences in adverse events among study groups. The high incidence of anemia seen in each group was likely related to ribavirin, which is no longer necessary in most chronic hepatitis C treatment [49c].

Sofosbuvir/velpatasvir/voxilaprevir Sofosbuvir (SOF)/velpatasvir (VEL)/voxilaprevir (VOX) is a novel, fixed-dose complete hepatitis C treatment regimen. It is the only regimen that contains an NS5B inhibitor, NS5A inhibitor plus a NS3/4A protease inhibitor co-formulated in a single tablet. This can be used as an alternative initial treatment in HCV genotype 3 if the patient has cirrhosis and Y93H resistance associated substitutions. More commonly, it is utilized in the setting of re-treatment or treatment failure [36S]. SOF/VEL/VOX remains the only treatment endorsed by the American Association for the Study of Liver Diseases and Infectious Diseases Society of America for treatment failure of patients who have had NS5A inhibitor experience, including patients who have failed ledipasvir/sofosbuvir or glecaprevir/pibrentasvir. SOF/VEL/VOX is extremely well tolerated. In currently available clinical trials, the most common adverse events from use of SOF/VEL/VOX included headache, fatigue, nausea and diarrhea [51R].

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICEINCY VIRUS: COMBINATIONS Bictegravir/emtricitabine/tenofovir alafenamide Bictegravir (BIC) in combination with tenofovir alafenamide (TAF) and emtricitabine (FTC) is available as a fixed dose combination regimen for the treatment of HIV. This

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single tablet regimen (STR) is a preferred, once daily therapy for antiretroviral-naïve patients and can also be utilized in patients who are virologically suppressed (HIV-1 RNA < 50 copies/mL) on a stable antiretroviral regimen for at least 3 months with no history of resistance to the individual components. BIC is a second-generation integrase inhibitor with a high in vitro genetic barrier to resistance that inhibits HIV integrase by binding to the integrase active site and blocking the strand transfer step of retroviral DNA integration into host cell DNA. Tenofovir alafenamide and FTC are both metabolized sequentially by intracellular kinases to the respective phosphorylated active moieties which have extended intracellular halflives. The main antiviral activity of TAF and FTC is through incorporation of the phosphorylated form into the viral DNA chain, resulting in chain termination [52S]. Bictegravir bares similarities in structure with dolutegravir and thus has similar side effects. Overall it has relatively few side effects and is generally very well tolerated. Common adverse events reported for BIC include headache, nausea and diarrhea, and the proportion of patients experiencing severe reactions never exceeds 1%. Creatinine elevations with a median of 0.10 mg/dL are the most frequently observed biochemical alternation due to BIC use without affecting renal glomerular function. Total bilirubin increases occurred in 12% of patients but were mild [53R,54R].

Doravirine/lamivudine/tenofovir dixoproxil fumarate (TDF) Doravirine is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) that is available alone or coformulated with tenofovir disoproxil fumarate (TDF) and lamivudine (3TC) in a single tablet regimen. Doravirine inhibits HIV-1 reverse transcriptase (RT) by binding to an allosteric site, known as the NNRTI binding pocket, causing conformational changes within the RT and inhibition of the polymerization reaction. The new pyridine structure allows it to demonstrate a broad spectrum of antiviral activity in vitro against a broad range of HIV-1 RNA viruses with transmitted NNRTI-resistanceassociated mutations that are increasingly found in treatment-naïve patients [52S]. In two phase 3 clinical trials DOR in combination with TDF/3TC proved to be non-inferior in virologic efficacy in HIV treatment-naïve patients when compared with ritonavir-boosted darunavir (DRV/r) based or Efavirenz based combination regimens regardless of CD4 count or viral load as well as in a switch study where patients were virologically suppressed (HIV-1 RNA <40 copies/mL) [55C,56C,57C].

Compared to other NNRTIs DOR has a more favorable safety profile. Preclinical safety studies demonstrate that DOR is not mutagenic or genotoxic in vitro genetic

toxicity assays. There were no embryo-fetal developmental toxicities and no effect on fertility of female and male rats. In dose-escalation studies in healthy males (single doses up to 1200 mg and multiple doses up to 750 mg daily up to 10 days) did not lead to rash, any significant central nervous system events (other than headache), or clinically meaningful corrected QT interval prolongation [58R]. The most common side effects observed in phase 3 clinical studies include diarrhea, nausea, and headache. In the DRIVE-FORWARD study DOR caused a statistically significant reduction in the fasting LDL cholesterol (LDL-C) and non-HDL cholesterol (HDL-C) compared to DRV/r-based regimens (P < 0.0001) [55C]. A mean change in serum creatinine occurred in 1% of patients on DOR ranging from 0.04 to 0.07 mg/dL. When compared to efavirenz based regimen in the DRIVE-AHEAD study, patients on DOR/3TC/TDF experienced a lower incidence of dizziness, sleep disturbances and altered sensorium (8.8% vs 37.1%, 12.1% vs 25.5%; and 4.7% vs 9.3%, respectively, all P < 0.0001). Fasting LDL-C and non-HDL-C were reduced by DOR/3TC/TDF and increased by EFV/FTC/TDF (both P < 0.0001) [56C]. Doravirine’s adverse effects are not enhanced or limited by food. Similar cholesterol effects were observed in the switch study, DRIVE-SHIFT. In this study, serious adverse events due to DOR occurred in 5 patients and they included elevations in alanine and aspartate aminotransferase, increased lipase, depression and renal failure [57C].

Darunavir/cobicistat/tenofovir alafenamide/ emtricitabine Darunavir/cobicistat (Drv/c) in combination with tenofovir alafenamide (TAF) and FTC is the only oncedaily single tablet regimen (STR) containing a boosted protease inhibitor. Based on two phase 3, non-inferiority trials, AMBER [59C] and EMERALD [60C], the STR known as Symtuza® received approval to be used in antiretroviral-naïve patients or patients who are virologically suppressed (HIV-1 RNA < 50 c/mL) for at least 6 months and have no resistance to DRV or tenofovir. This regimen combines two NRTIs, TAF (tenofovir formulation with an improved renal and bone density side effect profile) and FTC, the protease inhibitor with the highest barrier to genetic resistance, DRV, and the pharmacokinetic enhancer without antiviral properties, cobicistat [52S]. The single tablet regimen is generally well tolerated, with a tolerability profile consistent with that of individual components in both the AMBER and EMERALD trials. Adverse events (AEs) related to DRV/c/FTC/ TAF or comparator tenofovir DF-based therapy occurred in 35% and 42% of treatment-naive patients [59C] and 18% and 7% of treatment-experienced patients [60C],

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: NUCLEOSIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITORS (NRTI)

with the between-group difference being significant (P < 0.0001) in the latter study. Among these AEs, the most common with DRV/c/FTC/TAF included diarrhea (9% vs 11% with DF-based therapy), rash (6% vs 4%) and nausea (6% vs10%) in treatment-naive patients [59C] and diarrhea (2.1% vs 0.8% with tenofovir DF-based therapy) in treatment experienced patients [60C]. Serious adverse events included pancreatitis, psychiatric AE, increased alanine aminotransferase (ALT) and urticaria; however, the incidence was <1%. DRV/c/FTC/TAF was associated with more favorable measurement changes in renal function when compared with TDF based regimens; however, it is important to note that when patients were switched to DRV/c/FTC/TAF from DRV/r plus FTC/ TDF there were slight increases in SCr due to cobicistat’s ability to inhibit excretion of SCr and countering the effects of TAF [61R].

Abacavir/lamivudine/dolutegravir [SEDA-39, 275] The adverse effects of abacavir (ABC)/3TC/dolutegravir (DTG) were evaluated in a single-center, retrospective, pre- and post-analysis of incarcerated patients receiving care at an HIV telemedicine clinic at UIH between January 1, 2015 and June 30, 2017. Adult patients who switched from previous ART to ABC/3TC/DTG were included in the study. Primary endpoints included incidence of patient reported side effects and change in SCr, AST, and ALT from baseline. The secondary endpoint was evaluation of virologic suppression at baseline and after switch. After switching from previous ART to ABC/3TC/DTG, 20% (N ¼ 95) of patients reported side effects, with most common including headache (7.4%), nausea (6.3%), rash (3.2%), fatigue (3.2%) and insomnia (2.1%). There were statistically significant increases in SCr in 20% of the patients (P < 0.0001), with a median increase of 0.38 mg/dL. At the final follow-up visit, the proportion of patients with virologic suppression was similar before and after switching to abacavir/dolutegravir/ lamivudine (87% vs 86%) [62c].

Elvitegravir/cobicistat/FTC/tenofovir [SEDA-39, 275] A randomized, active controlled, multicenter, openlabel, non-inferiority trial, evaluated the efficacy and safety of EVG/c/TAF/FTC in virologically suppressed adult patients (HIV-1 RNA < 50 copies/mL) compared to TDF containing regimen. At 96 weeks, 93% of participants on TAF and 89% on TDF had HIV-1 RNA <50 copies/mL. Mean BMD at the hip and spine increased in the TAF group while remaining stable or decreasing at both sites in the TDF group at week 96 (P < 0.001) irrespective of previous treatment. More participants on TAF

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recovered from osteopenia or osteoporosis at either hip [TAF group 22.6% (58 of 257) vs TDF group 5.2% (7 of 134)] or spine [TAF group 20.4% (69 of 339); TDF group 9.4% (16 of 170)] by week 96 (P < 0.001 for difference in distribution of clinical BMD status). In participants who switched to TAF from a boosted regimen (i.e., excluding participants who switched from the unboosted regimen of EFV/FTC/TDF), mean (SD) serum creatinine decreased [by 0.04 (0.13) mg/dL] while remaining stable for the TDF group [0.00 (0.12) mg/dL; P < 0.001] at week 96. In those who switched from EFV/FTC/TDF, mean (SD) serum creatinine increased by 0.07 (0.13) mg/dL, whereas those remaining on EFV/FTC/TDF had a mean (SD) change of 0.03 (0.10) mg/dL, consistent with the established COBI effect on inhibition of serum creatinine excretion [63C]. A similar significant rise in SCr was shown in a prospective observational clinical cohort of people living with HIV initiating or switching to EVG/c/TAF/FTC based regimens in routine care in Germany [64c]. EVG/c/TAF/FTC proved to be safe and efficacious as a STR in HIV-1 infected adults with end-stage renal disease on chronic hemodialysis. In an open-label study, 55 virologically suppressed (HIV-1 RNA < 50 copies/ mL) participants who were on HD for >6 months (eGFR <15 mL/min) were switched E/C/F/TAF for 48 weeks. Through week 48, 18 of 55 participants (33%, 95% CI 20–45) had an adverse event of grade 3 or higher on study treatment. Treatment-emergent grade 3 or higher adverse events that occurred in more than one participant included anemia, osteomyelitis, prolonged electrocardiogram QT, fluid overload, hyperkaliemia, hypertension, and hypotension (all n ¼ 2). No adverse event of grade 3 or higher was considered by the site investigators to be treatment related. Three participants (5%, 95% CI 0–11) discontinued treatment because of adverse events; one of these (grade 1 allergic pruritus) was considered treatment related. Treatment-related adverse events were reported for six individuals (11%, 95% CI 3–19), the most common of which was nausea (in four individuals [7%]); all treatment-related adverse events were grade 1 or 2 in severity [65c].

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: NUCLEOSIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITORS (NRTI) [SEDA-35, 516; SEDA-36, 415; SEDA-37, 337; SEDA-38, 270; SEDA-39, 276] Abacavir [SEDA-35, 516; SEDA-36, 415; SEDA-37, 337; SEDA-38, 270; SEDA-39, 276] A rare adverse effect of abacavir is a life-threatening hypersensitivity reaction which is well-documented in

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patients positive for the HLA-B*5701 allele. Thus HLAB*5701 testing is required in all patients prior to starting ABC based regimen [52S]. A case of possible abacavirinduced hypersensitivity reaction was reported in an HLA-B*5701 negative patient. A 59-year-old, HIV positive Caucasian male, with HLA-B*5701 negative allele presented with sore throat, pruritic rash, myalgia and self-reported fever 3 weeks after initiation of ABC/DTG/3TC. Due to worsening clinical presentation and a Naranjo Adverse Drug Reaction Probability Scale score of 6 indicating a “probable” association with DTG/ABC/3TC, there was the immediate concern for an abacavir-induced hypersensitivity reaction, so the medication was immediately discontinued, and a repeat HLA-B*5701 test was ordered, but also returned negative. All symptoms resolved after several weeks, and his regimen was changed to EVG/c/FTC/TAF. The authors conclude that although abacavir-induced hypersensitivity reactions in HLA-B*5701 negative patients are extremely rare, hypersensitivity monitoring is necessary for all patients on abacavir [66A]. There is conflicting evidence on whether exposure to abacavir leads to an increased risk of myocardial infection (MI). A prospective observational study revealed an increased risk of coronary artery non-calcified/mixed plaques in patients exposed to regimens containing ABC. 403 participants of the Swiss HIV Cohort Study, who were 45 years old with no documented cardiovascular disease and estimated GFR (eGFR) > 60 mL/min were enrolled in the study. When compared to NRTIs (ABC, FTC, 3TC, TDF, AZT), NNRTIs (EFV), and PIs (ATV, DRV, LPV) ABC exposure was associated with non-calcified/mixed plaques (hazard ratio 1.46, 95% confidence interval [1.08–1.98]). TDF was negatively associated with any plaque (0.71 [0.51–0.99]) [67c]. A pooled meta-analysis found a comparable incidence rate of myocardial infection and cardiovascular events (CVE) among ABC-exposed and ABC-unexposed participants, suggesting no increased risk for MI or cardiovascular events (CVE) following ABC exposure in clinical trial populations. In 66 clinical trials, 13 119 adults (75% male, aged 18–85 years) were on ABC-containing combined antiretroviral (cART) and 7350 were not. Exposure-adjusted incidence rate (IR) for MI was 1.5 per 1000 person-years (PY; 95% confidence interval [CI], 0.67–3.34) in the ABC-exposed group and 2.18 per 1000 PY (95% CI, 1.09–4.40) in the unexposed group. The IR for CVEs was 2.9 per 1000 PY (95% CI, 2.09–4.02) in the exposed group and 4.69 per 1000 PY (95% CI, 3.40–6.47) in the unexposed group with studies of 48 weeks of follow-up, with a relative risk (RR) of 0.62 (95% CI, 0.39–0.98). The inclusion of nonrandomized and shorter-duration trials did not significantly change the RR for MI or coronary artery disease [68M].

Lamivudine [SEDA-35, 517; SEDA-36, 416; SEDA-37, 338; SEDA-39, 276] Lamivudine is a dideoxynucleoside analogue which undergoes intracellular phosphorylation to the putative active metabolite, lamivudine triphosphate. Lamivudine triphosphate prevents HIV replication by competitively inhibiting viral reverse transcriptase. 3TC is overall very well tolerated and is one of the essential NRTIs (combined with ABC or tenofovir) utilized in the treatment of HIV [52S].

Zidovudine [SEDA-35, 517; SEDA-36, 417; SEDA-37, 338; SEDA-39, 276] Zidovudine showed similar HIV protection to nevipraine (NPV) among formula-fed infants in Botswana. Utilizing data from the Mpepu study, a Botswana-based clinical trial investigating whether prophylactic co-trimoxazole could improve infant survival, a retrospective analysis was conducted evaluating mother to child HIV transmission events and Division of AIDS Grade 3 or Grade 4 occurrences of anemia or neutropenia among infants born full term (37 weeks gestation), with a birth weight 2500 g and who were formula fed from birth. A total of 695 (52%) of infants received AZT, while 646 (48%) received NPV from birth for at least 25 days but no more than 35 days. Confirmed intrapartum HIV infection occurred in two (0.29%) AZT recipients and three (0.46%) NVP recipients (P ¼ 0.68). Anemia occurred in 19 (2.7%) AZT vs 12 (1.9%) NVP (P ¼ 0.36) recipients. Neutropenia occurred in 28 (4.0%) ZDV vs 21 (3.3%) NVP recipients (P ¼ 0.47) [69c].

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: NUCLEOTIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITORS (NRTI) [SEDA-35, 516; SEDA-36, 415; SEDA-37, 337; SEDA-38, 270; SEDA-39, 276–277] Tenofovir [SEDA-35, 518; SEDA-36, 418; SEDA-37, 338; SEDA-38, 272; SEDA-39, 276–277] Renal toxicity Long-term renal effects of tenofovir disoproxil fumarate were evaluated in chronic HBV infected patients. This was a retrospective study of patients with chronic HBV who were treated with either TDF (n ¼ 239) or entecavir (ETV) (n ¼ 171), from 2000 through 2016. During a median follow-up of 43–46 months, of the patients with intact renal function at baseline (eGFR 60 mL/min/ 1.73 m2), there was no difference in renal function

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between the TDF and ETV groups at study completion. However, among patients with moderate renal impairment at baseline (eGFR <60 mL/min), patients exposed to TDF had significantly lower eGFR than the ETV group (44.7 vs 50.8 mL/min; P < 0.001). Also, in a subanalysis, patients older than age 60 years had worse renal outcomes with TDF compared with ETV [70C]. TDF associated nephrotoxicity is proportional to plasma TDF exposure. Compared to TDF, TAF has an enhanced stability in plasma leading to a lower systematic exposure and lower adverse effects [52S]. In a case series of 10 HIV and HIV/HBV-coinfected, multimorbid patients, who were switched to TAF based regimens due to prior TDF-associated kidney injury, renal function remained stable over the first year (median change in eGFR (IQR) at 12 months of 0.5 (3 to +3) mL/ min)), whereas proteinuria improved in several patients [71A]. In virologically suppressed Black adults, TAF in combination with FTC demonstrated improvements in renal and bone safety over TDF/FTC with similar sustained efficacy at week 96. This was a subgroup analysis by race for the efficacy (pre-specified) and safety (post-hoc) from a randomized, double blind, active controlled study in virologically suppressed HIV-infected individuals who switched to TAF/FTC from TDF/FTC while remaining on the same third agent. Of 663 treated patients, 136 (20.5%) self-identified as Black (FTC/TAF n ¼ 69, FTC/ TDF n ¼ 67). In Black patients on TAF, eGFR increased by 10.1 mL/min vs 4 mL/min on TDF (P ¼ 0.06) while in non-black patients eGFR increased by 10 mL/min on TAF vs 3.9 mL/min on TDF (P < 0.001). In the overall population, no cases of Fanconi syndrome or proximal renal tubulopathy occurred with FTC/TAF; one FTC/ TDF participant discontinued study drug due to proximal tubulopathy [72C].

baseline CKD, low body mass index, older age, and concomitant renally excreted medications [73A]. Another case of TAF induced kidney injury in an HIV/HCV coinfected patient is discussed in this case report [74A]. The first case of TAF induced Fanconi syndrome (FS) and nephrogenic diabetic insipidus (NDI) was reported. A 35-year-old with HIV, who was started on TAF 2 weeks prior, presented with weakness and falls for 3 days. Clinical presentation and laboratory values were indicative of FS and NDI. Immediately after discontinuation of TAF, the patient’s weakness, polyuria, and electrolyte disturbances resolved. The authors conclude that although TAF is reportedly less nephrotoxic than TDF, it may have similar renal tubular adverse effects as TDF [75A].

Despite TAF’s association with a lower incidence of renal adverse effects when compared to TDF, case reports of acute kidney injury and Fanconi syndrome (not observed during randomized clinical trials) have emerged. A 70-year-old man with HIV-1 infection, alcohol use disorder, chronic HCV infection, chronic kidney disease (SCr of 1.2 mg/dL and CrCl 50 mL/min at baseline) and Childs–Turcott–Pugh class B cirrhosis developed acute kidney injury (AKI) on TAF and cobicistat which was worsened by the initiation of Sofosbuvir (SOF) and Ledipasvir (LED). Patient’s SCr normalized after discontinuation of the HIV and HCV regimens and was subsequently switched to DTG/ABC/3TC for HIV and sofosbuvir–daclatasvir for HCV. Authors conclude that caution should be taken in using the combination of SOF/LED and EVG/c/FTC/TAF in patients with

Tenofovir alafenamide has shown an improved bone mineral density profile compared to TDF based regimens. In two international, randomized, double blind trials, patients with chronic hepatitis B (CHB) receiving TAF 25 mg had significantly smaller decreases in bone mineral density than those receiving TDF 300 mg in the hip (mean % change 0.00% vs 0.2.51%; P < 0.001) and lumbar spine (mean % change 0.075% vs 2.57%; P < 0.001), as well as a significantly smaller median change in eGFR by Cockroft–Gault method (1.2 vs 4.8 mg/dL; P < 0.001) at 96 weeks [77A]. Favorable bone mineral density results have also been observed in HIV-infected adolescents (12–18 years old) who switched from 2NRTIs to TAF/FTC while remaining on various third ARV agents (mainly efavirenz or LPV/r) in an open-label, 48-week trial over a period of 76 weeks [78c].

Bone density Among ARV agents TDF has been noted to decrease bone mineral density. A US national historical cohort of HIV-1 infected veterans evaluated TDF-associated fracture risk based on concomitantly administered ART. 4137 initiated EFV and 3024 initiated non-EFV regimens, including 232 with EVG/c, 171 with rilpivirine (RPV), and 2621 with ritonavir-boosted protease inhibitors (PIs). In adjusted analyses, EFV was associated with a statistically significant 31% lower risk of the composite bone outcome than non-EFV groups combined, 25% lower than RPV, and 30% lower than the ritonavir-boosted PI group. EFV was associated with a statistically significant 36% lower risk of osteoporosis than non-EFV groups combined, 53% lower than EVG/c, and 35% lower than the ritonavir-boosted PI group. The authors attribute the differences in outcomes to either CYP enzyme inhibition by ritonavir or cobicistat, or admiration of the TDF containing regimens with food, which lead to higher TDF exposure [76C].

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DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTI) [SEDA-35, 516; SEDA-36, 415; SEDA-37, 337; SEDA-38, 270; SEDA-39, 277–278] Efavirenz [SEDA-35, 519; SEDA-36, 420; SEDA-37, 339; SEDA-38, 273] Efavirenz is a first-generation NNRTI and a central component of ART regimens worldwide especially in resource limited settings. Common adverse effects include headache, insomnia, anxiety, vivid dreams, diffuse maculopapular rash, hyperlipidemia, and gastrointestinal effects. Neuropsychiatric adverse effects have deterred the use of efavirenz, especially in the United States. In a large observational cohort study conducted in the United States from 1999 to 2015 multiple clinical factors, including mental health were inversely associated with efavirenz use [79c]. In a randomized, open-label, controlled trial adults with HIV-1 RNA <50 copies/mL, who switched from efavirenz to rilpivirine based regimens (in combination with TDF/FTC) did not show a statistically significant difference in neurocognitive performance over a 24-week period. Depression and anxiety reduced over time, with no statistically significant difference between arms. A significant improvement in CNS symptoms, quality of sleep and self-reported cognitive failures was reported by patients in the switch but not in the continuation arm. No protocol defined virological failure, grade 3 laboratory abnormalities nor serious adverse events related to the study drugs were observed [80c].

These neuropsychiatric adverse events are also concerning for the pediatric population. A retrospective single-center case-note audit of children and adolescents with perinatally acquired HIV who received efavirenz was conducted to assess adverse events and reasons for discontinuation. 16 (out of 51, 30%) children and adolescents aged 18 years discontinued the drug due to adverse events. Of those, one-fifth (19.6%) described CNS adverse effects, including sleep disturbance, reduced concentration, headaches, mood change and psychosis. Four children (three males) developed gynecomastia, two developed hypercholesterolemia, and one child developed Stevens–Johnson syndrome. Comparison between those reporting side effects and the rest of the cohort showed no difference in age, sex, initial CD4 cell count, viral suppression, length of efavirenz-based treatment, weight, or efavirenz dose per kilogram. Median time to switch was 25 months (IQR 10–71) in those who experienced side effects and 22 months (IQR 12–50) for virological failure [81c].

A cross sectional observational study of HV infected children (6–12 years) on cART for 6 months and viral load 1000 copies/mL in Tanzania found no difference in emotional and behavioral problems, cognitive performance or adherence in patients receiving efavirenz based regimens vs control regimens; however, efavirenztreated children had lower school performance scores (P ¼ 0.025) [82c].

Nevirapine [SEDA-35, 521; SEDA-36, 421; SEDA-37, 339; SEDA-38, 274; SEDA-39, 278] A retrospective study evaluated the risk of hypertension in pregnancy by ARV regimen in Botswana. 5087 women were included who started ART prior to pregnancy with either AZT/3TC or TDF/FTC combined with either nevirapine (NVP), Lopinavir/ritonavir (LPV/r) or EFV. In adjusted analyses, women on NVP-based regimens were more likely to have hypertension (30% vs 16%), severe hypertension (3.3% vs 1.2%), gestational hypertension (18% vs 10%) and early gestational hypertension (12% vs 7%) compared with women on nonNVP based ARV. There was no difference in outcomes when NVP was combined with AZT/3TC vs TDF/FTC except for severe hypertension which was more common in AZT/3TC/NVP (6% vs 2%). Although hypertensive women on NVP accounted for only 13% of the population, they had 30% of the stillbirths [83C].

Rilpivirine [SEDA-35, 521; SEDA-36, 423; SEDA-37, 340; SEDA-38, 274; SEDA-39, 278] Rilpivirne is a well-tolerated second-generation NNRTI. PRO-STR was a 48-week prospective observational post authorization study conducted in 25 hospitals in Spain where patients switched to RPV/FTC TDF from either another NNRTI or ritonavir-boosted PI prior treatment due to adverse effects. A total of 303 patients were included (mean age 46.6 years; male 74.0%; previous treatment with NNRTI 74.7% and 25.3% PI/r). Prior to switching, the majority of the patients were on TDF/ FTC with efavirenz or ritonavir-boosted darunavir or atazanavir. At 48 weeks post switch, both groups exhibited significantly reduced lipid profiles, except for HDL cholesterol, for which a non-significant increase was observed. The most common intolerances (reasons for switching) were neuropsychiatric in the NNRTI patients and gastrointestinal and metabolic in the PI/r patients, and these intolerances were significantly reduced in both groups at week 48 [NNRTI: neuropsychiatric (baseline: 81.3%; week 48: 0.0%); PI/r: gastrointestinal (baseline: 48.7%; week 48: 0.0%) and metabolic (baseline: 42.1%; week 48: 0.0%)] [84C].

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: INTEGRASE STRAND TRANSFER INHIBITORS (INSTI)

A similar reduction in lipid parameters was observed in a prospective multicenter Italian study (SCOLTA) which evaluated the durability and safety of rilpivirine in patients who initiated or switched to a RPV based regimen. A slight but significant increase in AST (6  15 IU/mL, P < 0.0001 and 10  31 UI/mL, P ¼ 0.002) and ALT values (11  24 IU/mL, P < 0.0001 and 15  66 IU/mL, P ¼ 0.02) were observed at week 24 and 48, but not at week 72 in patients switching from a PI-based regimen (mainly occurring in HCV coinfected individuals) [85C].

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: PROTEASE INHIBITORS (PI) [SEDA-35, 516; SEDA36, 415; SEDA-37, 337; SEDA-38, 270; SEDA-39, 278] Atazanavir Ritonavir-boosted atazanavir (ATV/r) is a highly utilized protease inhibitor for HIV patients in resourcelimited settings. Common adverse effects include rash, hyperlipidemia, abdominal pain, jaundice, elevated liver function tests (LFT) and conjugated bilirubin levels. A rare but serious adverse event is cholelithiasis. Pharmacovigilance data from the WHO global data base revealed that children treated with ATV were more likely to present with hepatobiliary disorders compared to those treated with DRV (similar to adults) [86c]. The first case of atazanavir induced urothelial metaplasia along with chronic interstitial nephritis was reported in a virologically suppressed 48-year-old HIV positive male treated with TDF/FTC and ATV/r. On presentation the patient had a reduction in eGFR (from >90 to 32 mL/min) and histology of the kidney and ureters revealed hyperplasia, focal atypia and squamous metaplasia with no malignancy. Patient was subsequently switched from ATV/r to dolutegravir in combination with ABC/3TC and eGFR stabilized at 26 mL/min. The authors conclude that there are under-recognized risks of ATV-related nephrotoxicity, which can be linked to the cytotoxic effects (independent of large calculi formation) of the drug leading to renal injury and metaplasia [87A].

Darunavir Darunavir boosted by either ritonavir or cobicistat in combination with NRTIs is a widely utilized ARV regimen in both treatment naïve and experienced patients. Due to a more favorable side effect profile and higher genetic barrier to resistance Darunavir use is preferred over other protease inhibitors [52S].

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In a large, heterogenous, prospective, multicohort study the cumulative use of ritonavir-boosted darunavir, but not of ritonavir-boosted atazanavir, was associated with a small but progressively increasing risk of centrally validated cardiovascular disease. In the (D:A:D) study, during a median 6.96 years of follow-up, 1157 people (out of 357 111) developed cardiovascular disease (incidence rate 5.34 events per 1000 person-years; 95% CI 5.03–5.65). The incidence rate of cardiovascular disease progressively increased from 4.91 events per 1000 person-years (4.59–5.23) in individuals unexposed to ritonavir-boosted darunavir to 13.67 events per 1000 person-years (8.51–18.82) in those exposed to the drug for more than 6 years. The changes associated with ritonavir-boosted atazanavir were less pronounced, showing an incidence rate of 5.03 cardiovascular events per 1000 person-years (4.69–5.37) in unexposed individuals to 6.68 events per 1000 person-years (5.02–8.35) in participants exposed for more than 6 years. After adjustment, keeping factors on the potential causal pathway from boosted protease inhibitor use to cardiovascular disease fixed at baseline, ritonavir-boosted darunavir use was associated with increased risk of cardiovascular disease (incidence rate ratio 1.59; 95% CI 1.33–1.91 per 5 years additional use), but use of ritonavir-boosted atazanavir was not (1.03; 0.90–1.18). This association remained after adjustment for timeupdated factors on the potential causal pathway; myocardial infarction and stroke separately; plasma bilirubin concentration; and after stratification by use of ritonavir-boosted darunavir as the first ever protease inhibitor, used in combination with a non-nucleoside reverse transcriptase inhibitor, by previous virological failure, and by those at high risk of cardiovascular disease [88C].

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: INTEGRASE STRAND TRANSFER INHIBITORS (INSTI) [SEDA-35, 516; SEDA-36, 415; SEDA-37, 337; SEDA-38, 270; SEDA-39, 278–279] Integrase strand transfer inhibitors have revolutionized the treatment of HIV due to their high virologic potency and excellent safety profile. However, as their utilization has increased globally extensive postmarketing studies have revealed adverse events not observed during phase 3 randomized clinical trials. A prospective observational cohort study examined changes in weight and waist circumference in virologically suppressed adults (n ¼ 972, HIV-1 RNA < 200 c/ mL) from the AIDS Clinical Trials Group (ACTG) cohort who switched to an INSTI-containing regimen (68% from

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PI, 31% NNRTI, 2% other non-INSTI at median 7.8 years after parent trial entry) by comparing the trajectories (change of weight per year) 2 years before and after the switch. In adjusted models, white or black race, age 60 and BMI 30 kg/m2 were associated with greater weight gain following switch among women, whereas age 60 was the greatest risk factor among men. DTG was associated with the greatest increase in annual weight gain (1 kg per year (P ¼ 0.0009) vs 0.5 and 0.2 for EVG (P ¼ 0.11) and RAL (P ¼ 0.37), respectively). The authors conclude that following switch to INSTI annual within-person weight gain increased; however, the cardiometabolic implications of increased weight gain need to be established [89c]. Increased risk of weight gain after switching to INSTI based regimens have been described in several other observational studies [90c,91c,92c,93c]. In a randomized clinical trial (Gilead 1490) evaluating bictegravir/TAF/FTC to DTG with TAF/FTC there was a similar mean increase in body weight gain at 96 weeks (+3.5 kg vs +3.9 kg, respectively) [94C].

Dolutegravir Dolutegravir is a preferred INSTI with a high genetic barrier to resistance and is part of the recommended regimens for ART-naïve and ART-experienced patients. Dolutegravir is very well-tolerated and common adverse effects include as headache and nausea and diarrhea [52S]. Neurocognitive Increased rates of dolutegravir induced neuropsychiatric adverse effects (NPAEs) have been described in multiple observational studies conducted in Europe. A descriptive, retrospective, observational study of 292 HIV-infected patients initiated on DTG, revealed treatment discontinuation in 49 (16.78%) (median age 59 years (26–87), 65.3% males) patients. The majority (79.5%) of the patients were on concomitant ART with ABC/3TC and most of the patients (85.7%) discontinued treatment during the first year. In 18 out of 49 patients (36%) the reason for DTG discontinuation was neuropsychiatric AEs: insomnia (55.5%), anxiety, asthenia and nervousness (22.2%, respectively), dizziness (11.1%) and, less frequently, paranoid ideas and nightmares (5.6%). Neuropsychiatric AEs were more frequent in females (53%) than in males (28.1%), with a median age of 51 years (34–87). Neurotoxicity was reversible in 100% of patients when DTG was discontinued and more frequently in those receiving concomitant treatment with ABC/3TC (83.3%) [95c]. A case report of a 29-year-old Caucasian HIV positive female who experienced NPAEs (dizziness, fatigue, insomnia and restlessness) after 3 weeks of initiating

DTG/ABC/3TC revealed that supratherapeutic levels of DTG were contributory to the NPAEs [96A]. However, in a large cohort of HIV positive patients exposed to DTG in clinical routine, population plasma drug levels of patients who discontinued DTG due to NPAEs did not differ substantially from DTG exposed patients who did not discontinue the drug due to NPAEs. In this study 54 of 861 patients (6.3%) had discontinued DTG due to NPAEe, mainly sleep disorders (74%), dizziness (52%), and paresthesia (33%) after a median follow-up of 19.6 months, NPAEs leading to discontinuation were observed more frequently in women (hazard ratio [HR] 2.31; 95% confidence interval [CI] 1.12–4.74, P ¼ 0.03), in patients older than 60 years (HR 2.14; 95% CI 1.10–4.18, P ¼ 0.025), but not in patients with depressive disorders (HR 1.00; 95% CI 0.54–1.88, P ¼ 0.952) or other neuropsychiatric diagnoses (HR 0.93; 95% CI 0.29–3.00, P ¼ 0.896) [97C]. Other large observational cohort studies conducted in Europe found a low incidence of DTG induced NPAEs leading to discontinuation of the drug (approximately 2.7%–3.8%) [98C,99C,100c,101C]. Similarly, randomized clinical trials evaluating the use of dolutegravir based regimens have displayed a low incidence of NPAEs [102C]. In a phase 3, open-label, parallel-group, noninferiority, active controlled trial comparing the safety and efficacy of DTG to LPV/r plus two NRTIs, respectively, psychiatric adverse events were reported in 19 out of 312 (6%) participants receiving dolutegravir and 17 out of 312 (5%) receiving ritonavir-boosted lopinavir; none led to study withdrawal. Some participants who reported psychiatric adverse events had a history of psychiatric disorders at baseline. Insomnia was the most common psychiatric adverse event in both groups (eight [3%] receiving dolutegravir and seven [2%] receiving ritonavir-boosted lopinavir). Five participants had drug-related psychiatric adverse events, three (1%) receiving dolutegravir (insomnia, anxiety, and mental disorder caused by a general medical condition, one each) and two (1%) receiving ritonavir boosted lopinavir (both insomnia). Grade 3 psychiatric adverse events (depression, which was also considered a serious adverse event and suicidal ideation) occurred in two participants, both of whom were receiving dolutegravir. Neither adverse event was considered treatment related. No grade 4 psychiatric adverse events were reported [103C]. Neural tube defects (NTD) Preliminary data from the observational surveillance study of birth outcomes among pregnant women on ART in Botswana (Tsepamo study) identified NTDs in four infants born from 596 women (0.67%) who initiated a DTG based regimen prior to pregnancy, and who were still receiving it at the time of conception. The incidence of NTDs among infants born to women who were receiving other ARV drugs at the time of conception was 0.1%. One

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infant experienced NTD when the mom initiated DTG during pregnancy (8-weeks gestation). The authors conclude that this is an early signal for increased prevalence of neural tube defects in association with DTG based ARV, however, given the small number of events and the small difference in prevalence more data are needed to confirm or refute the signal [104c,105c].

Raltegravir The approval of raltegravir (RAL) as the first integrase inhibitor brought hope to patients living with HIV worldwide. Due to its efficacy and very well tolerated safety profile RAL in combination with NRTIs is part of preferred regimens throughout the world. Observational studies A retrospective cohort study of HIV infected adults in a large integrated healthcare system was conducted from 2005 to 2013. The study compared patients initiating RAL during the study period with two groups; a historical cohort (started new antiretroviral regimen [ART] 2005–07) and a concurrent cohort that did not initiate RAL (2007–13). The population included 8219 HIVinfected adults (RAL cohort N ¼ 1757; 4798 patientyears), with greater years known HIV-infected among RAL patients. The RAL cohort showed an increased hazard ratio (HR) for AIDS-defining (HR 2.69 [1.53–4.71]; HR 1.85 [1.21–2.82]) and non-AIDS-defining malignancies (HR 2.26 [1.29–3.94]; HR 1.88 [1.26–2.78]) relative to both comparison cohorts. Compared to the historical cohort there was no significant difference in all-cause mortality; the RAL cohort experienced increased HR for all-cause mortality compared to concurrent (HR 1.53 [1.02–2.31]). Raltegravir appeared protective of lipodystrophy when compared to the historical cohort but associated with increased incidence compared to concurrent. There were no significant differences in the incidence of hepatic, skin, or cardiovascular events [106c]. In contrast, a retrospective historical study utilizing the EuroSida cohort found no evidence for an oncogenic risk or poorer survival associated with RAL compared with control groups. The cohort was divided into three groups: those starting RAL-based combination antiretroviral therapy (cART) on or after December 21, 2007 (RAL); a historical cohort (HIST) of individuals adding a new antiretroviral (ARV) drug (not RAL) to their cART between January 1, 2005 and December 20, 2007, and a concurrent cohort (CONC) of individuals adding a new ARV drug (not RAL) to their cART on or after 21 December 2007. The RAL cohort included 1470 individuals [with 4058 person-years of follow-up (PYFU)] compared with 3787 (4472 PYFU) and 4467 (10 691 PYFU) in the HIST and CONC cohorts, respectively. The prevalence of non-AIDS-related malignancies prior to baseline tended

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to be higher in the RAL cohort vs the HIST cohort [adjusted odds ratio (aOR) 1.31; 95% confidence interval (CI) 0.95–1.80] and vs the CONC cohort (aOR 1.89; 95% CI 1.37–2.61). In intention-to-treat (ITT) analysis (events: RAL, 50; HIST, 45; CONC, 127), the incidence of all new malignancies was 1.11 (95% CI 0.84–1.46) per 100 PYFU in the RAL cohort vs 1.20 (95% CI 0.90–1.61) and 0.83 (95% CI 0.70–0.99) in the HIST and CONC cohorts, respectively. After adjustment, there was no evidence for a difference in the risk of malignancies [adjusted rate ratio (RR) 0.73; 95% CI 0.47–1.14 for RAL vs HIST; RR 0.95; 95% CI 0.65–1.39 for RAL vs CONC] or mortality (adjusted RR 0.87; 95% CI 0.53–1.43 for RAL vs HIST; RR 1.14; 95% CI 0.76–1.72 for RAL vs CONC) [107C].

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: INHIBITOR OF HIV FUSION [SEDA-35, 516; SEDA-36, 415; SEDA-37, 337; SEDA-38, 270; SEDA-39, 278] Enfuvirtide Fusion inhibitors are a class of molecules designed to disrupt the HIV envelope from merging with the host CD4 + cell membrane. HIV binds to the host CD4 + cell receptor via the viral protein gp120 and gp41, and then undergoes a conformational change that assists in the fusion of the viral membrane with the host cell membrane. Enfuvirtide (also known as T20) is a 36-amino-acid peptide that binds to gp41 and thus preventing the formation of an entry pore for the capsid of the HIV-virus. Common side effects with enfuvirtide include injection site reactions, diarrhea, fatigue and nausea [108r].

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: CHEMOKINE RECEPTOR CCR5 ANTAGONIST [SEDA-35, 516; SEDA-36, 415; SEDA-37, 337; SEDA-38, 270; SEDA-39, 279] Maraviroc Maraviroc (MVC) is an entry inhibitor utilized for the treatment of HIV. Binding of MVC to CCR5 prevents interaction with the third hypervariable loop (V3 loop) of the viral envelope protein gp120 and thereby prevents HIV entry into the cell. The safety and efficacy of maraviroc were evaluated in a 96-week, open-label switch study of virologically suppressed patients (HIV-1 RNA < 50 copies/mL) previously treated with two NRTIs and a ritonavir-boosted PI (PI/r). Virologic suppression was maintained in

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89% and 90.4% of patients who continued PI based regimen or switched to MVC based regimen, respectively.

Seventy-nine percent of the PI/r arm and 87% of the MVC arm (P ¼ 0.146) reported at least one adverse event during the study; of these, none were grade 4. Of the 863 events reported, the majority were either grade 1 (total 542 adverse events; 204 in the PI/r arm and 338 in the MVC arm) or grade 2 (total 304; 85 in the PI/r arm and 219 in the MVC arm). Adverse events leading to a change in study medication occurred in none of the PI/r participants and three of the MVC group (P ¼ 0.553). Overall, there were 28 (12%) serious adverse events reported, 10 (12%) in the PI/r arm and 18 (11.5%) in the MVC arm, respectively; none was considered related to the study drug. Over 96 weeks, the MVC arm had a mean decrease in total cholesterol (0.46mmol/L), triglycerides (0.41mmol/L) and low-density lipoprotein (LDL) cholesterol (0.22mmol/L); these declines were significant for both total cholesterol (P ¼ 0.0229) and triglycerides (P < 0.001), with a trend towards significance for the changes in LDL cholesterol (P ¼ 0.0916) compared with the PI/r arm [109C].

DRUGS ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS: CD4DIRECTED POST ATTACHMENT INHIBITOR Ibalizumab Ibalizumab (IBA), a humanized immunoglobulin (Ig) G4 monoclonal antibody (MAB) derived from mouse MAB 5A8 binds CD4 extracellular domain 2, thereby preventing conformational changes in the CD4-HIV envelope glycoprotein (gp120) complex that are essential for viral entry. Ibalizumab is reserved as an add-on therapy for heavily treatment-experienced adults who are failing their current antiretroviral regimen [110R]. In a phase 3, open-label, single arm study intravenous IBA was generally well tolerated with at least one adverse event occurring in 32 (80%) patients. The majority of the adverse events (87%) were mild to moderate in severity and mainly included diarrhea (20%), nausea, fatigue, pyrexia, rash, dizziness (13% for each). A total of 22 serious adverse events occurred in 9 (23%) patients and out of these only one (immune reconstitution inflammatory syndrome (IRIS) was considered to be related to ibalizumab therapy. This resulted in drug discontinuation and the addition of such warning to the drug label. No reports of hepatotoxicity, cancer, or infusion site reactions related to ibalizumab treatment were noted, and none of the patients developed anti-ibalizumab antibodies during the study period [111C].

DRUGS ACTIVE AGAINST INFLUENZA VIRUSES: NEURAMINIDASE INHIBITORS [SEDA-35, 528; SEDA-36, 431; SEDA-37, 344; SEDA-38, 277; SEDA-39, 279–280] Oseltamivir The most common adverse effects are nausea, vomiting, and headache [112S]. However, available data suggest that oseltamivir can cause more serious adverse effects, which are grouped into either sudden-onset or delayed-onset. The sudden-onset type adverse effects include not only nausea, vomiting, and hypothermia, but also neuropsychiatric reactions, such as abnormal behaviors, hallucination, and sudden respiratory arrest, then cardiac arrest and death [113R]. They usually occur in children less than or equal to 16 years of age within 48 h of taking the drug [114R]. These sudden-onset type adverse effects are evident from previously published data [115A,116A,117A]. Interestingly, short-term use of oseltamivir was significantly associated with increased risk of neuropsychiatric adverse events in a population-based, case-crossover study [118c]. Neuropsychiatric adverse effects have been observed when oseltamivir was used as a prophylaxis against influenza as well. A review of four randomized trials demonstrated that oseltamivir prophylaxis was significantly associated with neuropsychiatric adverse effects, particularly with those defined as severe [119M]. Although neuropsychiatric adverse effects from oseltamivir can be severe, it has not been associated with increased risk of suicide in children [120c]. The delayed-onset type of oseltamivir adverse effects includes psychosis and other psychiatric reactions, and renal, metabolic (hyperglycemia), and cardiac (QT prolongation) reactions [112S]. For instance, there is a recent case of a 5-year-old boy who developed sinus bradycardia after receiving oseltamivir [121A]. Rare adverse effects from oseltamivir have been recently reported as well. A 53-year-old male received oseltamivir for suspected influenza. On day 3, he experienced myalgia and dark urine. His creatine kinase (CK) was highly elevated, which led to the diagnosis of rhabdomyolysis. He was placed on intravenous hydration, and CK level started to drop on day 16 [122A]. Another case involved a 6-year-old boy who had elevated ALT and AST on day 2 of starting oseltamivir. By day 15, ALT further increased with elevated total bilirubin. The patient did not have any severe symptoms of hepatic disease except fatigue and yellowing of his skin and sclera. The liver enzyme tests returned to normal after 6 weeks of treatment with glucocorticoid [123A].

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Zanamivir Zanamivir is very similar to oseltamivir and shares similar side effect profile, including neuropsychiatric reactions. Bronchospasm may occur, particularly in patients with asthma or chronic obstructive pulmonary disease [124S].

Peramivir Peramivir has the same mechanism of action as oseltamivir and zanamivir; therefore, neuropsychiatric adverse effect is always a concern [125S,126c]. In a multicenter, randomized, comparative study with high-risk influenza-infected patients, oseltamivir group experienced more adverse effects than peramivir group in which only one patient had pneumonia or bronchial asthma attack [127C]. A systematic review and meta-analysis found that severe adverse events occurred similarly between peramivir and oseltamivir groups. Both groups experienced nausea, vomiting, and diarrhea most commonly [128M]. In a prospective observational study based on post-marketing surveillance data, the most common adverse events from peramivir were fever, diarrhea, nausea, and pneumonia. Patients with influenza complications, underlying diseases, and concomitant medications experienced adverse events more frequently [129c]. Then, a retrospective cohort study evaluated elderly patients over 65 years of age who had at least one underlying disease and hospitalized with influenza. Overall, 18.4% of the patients had adverse events, including loss of appetite, diarrhea, poor balance, rash, thrombocytopenia, and elevation of CK [130c]. Interestingly, there is a report of a 44-year-old male who developed severe immune thrombocytopenia from peramivir use. Thrombocytopenia resolved after the treatment with prednisolone [131A].

DRUGS ACTIVE AGAINST INFLUENZA VIRUSES: SELECTIVE CAP-DEPENDENT ENDONUCLEASE INHIBITOR Baloxavir A double-blind, placebo- and oseltamivir-controlled, randomized, phase 3 trial (CAPSTONE-1) was conducted in which adverse events occurred similarly among baloxavir, oseltamivir, and placebo groups. There were two serious adverse events in baloxavir group, including incarcerated inguinal hernia and aseptic meningitis; however, they were not considered to be related to baloxavir by the study investigators. Drug-related adverse events were more common with oseltamivir than baloxavir or placebo. The most common baloxavir-related adverse events were diarrhea and nausea [132C]. A recent systematic review and meta-analysis showed that baloxavir was

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not significantly different from neuraminidase inhibitors for safety, but it had less total drug-related adverse events [133M].

DRUGS ACTIVE AGAINST INFLUENZA VIRUSES: PROTEIN 2 CAP-BINDING INHIBITOR Pimodivir In TOPAZ trial, a phase 2b, randomized, doubleblinded, placebo-controlled, parallel-group, dose– response, multicenter of study, mild to moderate diarrhea was the most common adverse event. The higher the dose of pimodivir, the more frequent the diarrhea was. A patient who received 300 mg of pimodivir had insomnia, which was considered possibly related to the drug, and paresthesia probably related to the drug. With pimodivir 600 mg, liver enzyme elevation was probably related to the drug, and low ANC and low neutrophils were possibly related to the drug. Adverse events related to pimodivir when it was combined with oseltamivir were ALT elevation, urine protein level elevation, absolute neutrophil count reduction, white blood cell count reduction, GI events (i.e., nausea, vomiting, abdominal cramps, diarrhea), and sinus bradycardia. There were two serious adverse events in the study: ALT elevation that resolved 21 days after pimodivir 600 mg and thrombocytopenia from placebo [134C].

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