Zovirax

By P. Mason. Uniformed Services Universty of the Health Sciences. 2018.

The extension of the prophylactic scheme (Tables 5 and 6) is important if viral load in a high HIV transmission risk is not under 50 copies/ml at the time of delivery or 12 weeks before delivery has not yet been under 50 copies/ml purchase 200mg zovirax amex. On the other hand in pregnancies with an increased transmission risk with a viral load of <50 copies/ml at least 12 weeks before delivery a mono-prophylaxis with AZT for 2–4 weeks is sufficient for the newborn 800mg zovirax overnight delivery. HIV and Pregnancy 539 Table 5: Prophylaxis in the case of increased transmission risk Increased risk Mother Child Multigravidity Combination, e. Although speci- ficity is high, it is still considered inadequate. The combined use of two rapid tests from different manufacturers is ideal. If one of the two tests is negative, there is prob- ably no infection. Table 6: Prophylaxis when transmission risk is highly increased and VL is >50 copies/ml Highly increased risk Mother Child Premature infants <33+0 weeks In addition to AZT or AZT (dosage, see above) over of gestation and VL >50 copies/ml combination therapy: 4–6 weeks plus (or VL <50 for less than 12 weeks) nevirapine* 3TC** 2 x 2 mg/kg over 4–6 weeks plus Premature rupture of membranes nevirapine* 2 mg/kg within 2–48 h >4 hours + 2nd dose 48–72 h postpartum Amniotic infection syndrome (if no NVP prepartum or <2h between Rise of viral load towards the ingestion and delivery) end of pregnancy (If prepartum nevirapine, then only 1x after 48–72 h)*** Incision injury of the child As above Ingestion of hemorrhagic amniotic fluid HIV diagnosed only post partum * See chapter NNRTIs. In Germany, the duration of the oral standard pro- phylaxis has been shortened from six to two (or four) weeks (Vocks-Hauck 2001, Neubert 2013). Increased transmission risk (multiple neonates, premature infants) In multiple-birth neonates without further risk, a two- to four-week AZT prophylaxis is recommended (without nevirapine). Premature infants (>33+0 weeks and VL >50 copies/ml and <33 weeks and VL <50 copies/ml) receive AZT monoprophylaxis for 6 weeks, if VL is <50 copies/ml at least 12 weeks before delivery. Highly increased transmission risk An additional transmission risk exists, e. A strongly increased risk exists, for example: • after premature rupture of membranes • in cases of amniotic infection syndrome • when viral load >10,000 copies/ml prior to delivery • when there has been no transmission prophylaxis • if an incision injury of the child during cesarean section • if the amniotic fluid sucked from the gastrointestinal or respiratory tract of the newborn is hemorrhagic • if maternal viral load has been more than 50 copies/ml In the case of children with additional transmission risks, a combination prophy- laxis of AZT+3TC, as well as two doses of nevirapine are recommended. Nevirapine is given either once to the mother before delivery and once to the infant, or twice postnatally. If maternal nevirapine administration occurs less than an hour before delivery, then the newborn receives its first dose within the first 48 hours (Stringer 2003). If nevirapine was a part of the combination therapy for the mother, the dose is doubled to 4 mg/kg in newborns because of possible enzyme induction. In addi- tion, newborns receive an AZT+3TC prophylaxis for six weeks (CDC 2014). The pharmacokinetic data on ART in neonates are, however, extremely limited. According to the CDC guidelines (2014) the prenatal nevirapine dose to the mother is not applicable. Therefore the newborn receives nevirapine three times in the first week: immediately after birth and then after 48 and 96 hours. In addition, to lower toxicity only AZT is recommended as post-exposition prophylaxis for six weeks (two-drug regime, CDC 2014). In neonates whose mothers did not receive ART, prophylaxis with a two- or three drug regimen is superior to zidovudine alone (Nielsen Saines 2012). No differences were observed between single and combina- tion neonatal drug prophylaxis in infants at high risk for MTCT in a European study (Chiappini 2013). According to an FDA Safety communication (2011), lopinavir/r should not be admin- istered to (premature) newborns during the first two weeks due to cardiotoxicity (McArthur 2009). Furthermore, transient adrenal insufficiency has been reported in newborns who have been exposed to lopinavir/r prenatally and for 30 days postna- tally (Siman 2011). As such, lopinavir/r is no longer given to newborns in the first two weeks. HIV and Pregnancy 541 Raltegravir-based therapy induces rapid viral decay after short course treatment in late pregnancy (British Guidelines 2012), but may increase the risk of bilirubin neu- rotoxicity (Clarke 2013+2014). Procedure in cases of no pre- or intranatal prophylaxis Combination prophylaxis of AZT+3TC should start within the first 6 to 12 hours after delivery. In addition, a perinatal nevirapine prophylaxis is recommended. If HIV infection is discovered only after birth, a combination prophylaxis, begun within 48 hours, seems to be far more effective than a monoprophylaxis which is initiated only after 3 days (transmission rates 9. However, even then, a certain positive effect of AZT prophylaxis as opposed to no prophylaxis can still be verified (18. Even a late initiation of postnatal pro- phylaxis (>3 days) can still make sense. Table 7: Studies on antiretroviral prophylaxis in neonates Abbreviated Average Most frequent Studies name daily dose side effects AZT, Retrovir 4 x 2 mg/kg, 2 x 2 mg/kg GI, anemia, neutropenia (P)ACTG 076, 316, in PI* <35 GW, from 15th day: Mitochondriopathy in 321, 353, 354, 358; 3 x 2 mg/kg*, combination with 3TC HIVNET 012 III in PI <30 GW from 29th day PACTG 331(PI) 3TC, Epivir 2 x 2 mg/kg in neonates GI, vomiting, mitochondrio- PACTG 358 (<30 days) pathy in combination, incompatibility in premature infants FTC, Emtriva 3 mg/kg in neonates Minimal toxicity, ANRS 12109, to <3 months mitochondriopathy Gilead PK study ddI, Videx 2 x 50 mg/m2 from 14thday Diarrhea, pancreatitis, PACTG 239, 249; mitochondriopathy HIV-NAT in combination d4T, Zerit 2 x 0. Antiretroviral agents that are not approved should not be used in neonates (except for clinical studies) Further studies for HIV prevention in neonates A survey of studies of the pharmacokinetics in pregnancy and neonates is listed in Table 7 (Ronkavilit 2001+2002, Blum 2006, Chadwick 2008, Hirt 2009a+b, Mirochnik 2005+2014). In order to continuously improve ART during pregnancy and the pro- phylaxis of perinatal HIV infection, a thorough documentation of clinical data is necessary. In the US, the Antiretroviral Pregnancy Registry is an extensive therapy register that helps to evaluate the potential teratogenicity of antiretrovirals on the basis of case reports of HIV-exposed neonates: Antiretroviral Pregnancy Registry, Research Park, 1011 Ashes Drive, Wilmington NC 28405.

Dependent on the use of coreceptors (“tropism”) the virus is classified as CCR5-(“R5”-) tropic or CXCR4- (“X4”-) tropic generic zovirax 400 mg fast delivery. Viral strains using both coreceptors are called dual-tropic purchase 400mg zovirax with mastercard. Since tropism tests cannot distinguish between dual-tropic viral isolates and a mixture of R5- and X4-tropic viral isolates, the term dual/mixed (D/M) tropic is used. Analogous to resistance testing, tropism testing can be performed genotypically or phenotypically (Braun 2007). European guidelines recommend both the enhanced sensitivity Trofile assay and V3 loop population sequencing (Vandekerckhove 2011). Table 4 outlines the advantages and disadvantages of both methods. Phenotypic tropism testing Due to its use in clinical trials, TrofileTM is the best-known phenotypic tropism test. TrofileTM ES (TrofileTM with enhanced sensitivity) detects minor viral populations down to a 1% sensitivity. This test has further become available for the use of provi- ral DNA when viral load is <1000 HIV RNA copies/ml. Another commercially avail- able phenotypic test is Phenoscript ENV (EuroFins/VIRalliance). An 85% agreement between both assays has been reported (Skrabal 2007). Other non-commercial phe- notypic assays have been developed (Mulinge 2013). Genotypic tropism testing For genotypic tropism analysis, the V3 domain of the gp120 gene – which is crucial for coreceptor binding and encodes for the viral tropism – is sequenced. This gene sequence primarily defines the viral tropism, though other gp120 regions such as V1/V2 and C4 as well as substitutions at gp41 also play a role. With viral loads between 50 and 200 HIV RNA copies/ml, the preferred method is population-based sequencing of the V3 loop from proviral DNA. Web-based bioinformatic tools are used to predict viral tropism from the respective nucleotide sequence. These tools use methods like the charge rule, support vector machines or decision trees (Garrido 2008). The most popular tropism prediction tools geno2pheno [coreceptor] and WebPSSM are available free of charge: • geno2pheno [coreceptor] http://coreceptor. In contrast to phenotypic analysis, geno- typic analysis cannot distinguish between X4-tropic and dual-tropic or mixed pop- ulations. The result of the geno2pheno [coreceptor] tool is the so-called false posi- tive rate (FPR), which is the probability of classifying an R5 virus falsely as X4. HIV Resistance and Viral Tropism Testing 305 The current FPR cut-offs recommended in national and international guidelines range between 5-10% for X4 prediction and 10–20% for R5 prediction. For tropism testing from proviral DNA, which is used in case of undetectable viral load or low level viremia, the same FPR cut-offs can be used. The European guidelines recommend triplicate PCR amplification and sequencing (which is expensive and labor-inten- sive). The corresponding FPR when using the geno2pheno [coreceptor] interpreta- tion tool should be 10% to discriminate between R5- and X4-tropic virus. In case of single testing the FPR should be increased to 20% (Vandekerckhove 2011). The German guidelines do not recommend multiple testing. For R5 and X4 prediction an FPR of 15% and 5% are recommended, respectively. For indeterminate results between 5 and 15% the use of CCR5 antagonists should be carefully weighed against other therapeutic options (Walter 2012). Ultrasensitive sequencing As for genotypic resistance testing, there are standard population sequencing (detect- ing X4-tropic virus variants if they comprise at least 20% of the total virus popula- tion) and ultrasensitive methods (such as ultra-deep sequencing with detection limits of a few percent or less). In a study of ART-naïve patients treated with maraviroc plus atazanavir/r, TrofileTM ES was used for tropism testing. All samples were analyzed using population sequenc- ing (PS) and ultra-deep sequencing (UDS) with FPRs of 5. In 199 paired results, a concordance with Trofile ES of 91. Samples, which were classified as non-R5 using Trofile ES and as R5 using PS had a mean proportion of 2. Comparison of genotypic and phenotypic tropism testing The advantages of genotypic tropism testing are its wide availability and the rapid results.

In a small study (n=40) purchase zovirax 400 mg without prescription, similar rates of unspecified gastrointestinal adverse effects and headache were reported between the group using CEE and the placebo group (no 35 statistics provided) cheap zovirax 800 mg fast delivery. In the WHI (see Table 11, summary table), vaginal bleeding was frequent among the 81 CEE plus MPA treatment group, occurring in 42. In contrast, reports of bleeding never exceeded 8% in the placebo group. Among women asymptomatic at baseline, the treatment group also reported more breast tenderness at 1- year follow-up (CEE+MPA 9. This group also reported more vaginal discharge (CEE+MPA 4. In Update #3, six new trials were identified which examined the effects of hormone 26, 31, 32, 40, 43, 78 therapy on cognitive function with follow-up between 12 weeks and 3 years, all demonstrating no differences between groups at up to 2-year followup. The fair-quality ULTRA 78 trial found no significant differences at 2-year follow-up between treatment with low-dose transdermal estradiol and placebo for multiple measures of cognitive function: Mini Mental Hormone therapy Page 51 of 110 Final Report Update 3 Drug Effectiveness Review Project State Exam, logical memory, Brief Visual Spatial Memory Test, memory and recall of words, and verbal fluency. Similar negative results were found in a small, fair-quality study of estradiol 32 patch. In the fair quality study (n=373), the Folstein Mini-mental State Examination did not differ between the hormone replacement group (conjugated equine estrogen with or without progesterone depending on uterine status) and placebo at 3-year follow-up. Self-reported 31 function and physical activity levels also did not differ significantly between groups. A poor-quality study did not find differences between treatment group for multiple measures of 43 cognitive function either. A fair-poor quality study reported improvement in 1 of 5 measures 40 of cognitive function at 12-week follow-up (p=0. What is the comparative safety of different hormone therapy preparations for long-term use (5 or more years)? Summary points - In the WHI CEE/MPA study, coronary heart disease (CHD) events increased significantly, although CHD mortality did not at 5. In the WHI CEE-only study, CHD events were not increased. Global cognitive function and mild cognitive impairment did not differ from placebo groups in either WHI study. Rates of cardiovascular mortality were not increased - In the WHI CEE-only study, a significant increase was noted in the hazard ratio (unadjusted for multiple comparisons) for stroke and venous thromboembolism. Rates of probable dementia, cardiovascular events or mortality, and invasive breast cancer were not increased. The WHI was designed as a primary prevention trial, not a trial of menopausal symptom treatment. Hormone therapy Page 52 of 110 Final Report Update 3 Drug Effectiveness Review Project Table 10. Women’s Health Initiative: Summary of the adverse effects Outcome CEE+MPA (5. Mortality from coronary heart disease events was not elevated, however (HR 1. Events occurred early in the trial and persisted throughout the 5. No interaction was found for age, race, BMI, smoking status, blood pressure, diabetes, statin use, or the effect of CEE/MPA on CHD events. Absolute increases in coronary heart disease cases were estimated at 7 per 10,000 person-years. Among the small subgroup with established CHD at baseline (n=400), the HR was 1. Total mortality was also not significantly different between treatment groups. Among women with prior myocardial infarction or revascularization procedures, the effect of CEE compared to placebo on CVD event rates did not differ from the effect among women without known CHD. The WHI study examined a global index of risks and benefits which was defined for each subject as the time to the first event among the monitored outcomes, including CHD, stroke, 80 pulmonary embolism, breast cancer, colorectal cancer, hip fractures, and death. This measure 4 was used to assess the overall balance of risks and benefits and was balanced overall (HR 1. CEE did not affect total mortality or cause-specific mortality. All participants had documented coronary heart disease at randomization. The unadjusted relative hazard (HR) Hormone therapy Page 53 of 110 Final Report Update 3 Drug Effectiveness Review Project for CHD events was not different from placebo (HR 1. In post hoc analyses, the HR for the first year of treatment was 1. Stroke Risk for stroke was elevated in the WHI for CEE/MPA compared to placebo (HR 1. A systematic review and meta-analysis of other studies of estrogen and stroke 201 reported a significant increase in stroke risk (RR 1. Absolute 4 increases in stroke are estimated at 8 per 10,000 person-years using WHI estimates.

Rates of serious adverse events were not different from placebo in any trial discount zovirax 800 mg amex, and rates of depression were not significantly higher than placebo in the 2 trials reporting this outcome (interferon beta-1b ® ® (Betaseron ) and interferon beta-1a (Avonex ) purchase 400 mg zovirax with visa. Disease-modifying drugs for multiple sclerosis Page 54 of 120 Final Report Update 1 Drug Effectiveness Review Project Table 22. Adverse events of beta interferons in patients with a clinically isolated syndrome Interferon Adverse event rates Study Dose/schedule Withdrawal due to adverse events Treatment vs. In a 5-year, open-label extension arm of the CHAMPS study, only serious adverse events (N=13 in 6% of patients overall) were reported and none were considered related to interferon 123 beta-1a. Other typical and concerning adverse events associated with interferon beta-1a were not discussed or reported. In the 5-year follow-up phase of the BENEFIT trial, the incidence and nature of adverse events was similar to that reported at the end of the 2-year placebo-controlled Disease-modifying drugs for multiple sclerosis Page 55 of 120 Final Report Update 1 Drug Effectiveness Review Project period. More patients in the delayed treatment group discontinued due to adverse events (12% 129 compared with 2%). Do disease-modifying treatments for multiple sclerosis differ in harms? Summary of the Evidence Adverse events and long-term safety Beta interferons • Comparative adverse event reporting was limited with multiple studies using different ® doses of the same product, most frequently with interferon beta-1a SC (Rebif ). We have ® used data pertaining to interferon beta-1a SC (Rebif ) 44µg SC 3 times weekly dosing when pooling all trial data. Comparative tolerability of beta interferon Adverse event Relative frequencies based on pooled trial rates ® ® Interferon β-1a SC (Rebif ) 60. Disease-modifying drugs for multiple sclerosis Page 56 of 120 Final Report Update 1 Drug Effectiveness Review Project • Elevated liver enzymes were also very common among beta interferon-treated patients, particularly during the first year of treatment. Withdrawal rates due to elevated liver enzymes were very small across the trials. Glatiramer acetate • Tolerability adverse events were reported in 2 head-to-head trials comparing glatiramer acetate to beta interferon products. They revealed similar tolerability with glatiramer acetate having higher rates of injection site reactions and post-injection systemic response while the interferons reported higher rates of flu-like syndrome, elevated liver enzymes, fever, myalgia, and headache. Lipoatrophy was reported only in patients receiving glatiramer acetate. No additional serious adverse events were reported in any of these studies, with the exception of the risk of potentially permanently disfiguring lipoatrophy with glatiramer acetate use. Natalizumab ® • Natalizumab (Tysabri ) use has been linked to 55 cases of progressive multifocal leukoencephalopathy worldwide. Two cases of progressive multifocal leukoencephalopathy led to cessation of 1 of these trials (SENTINEL). There is now a black box warning issued by the US Food and Drug Administration due to reported cases of progressive multifocal leukoencephalopathy associated with natalizumab use with risk being directly proportional to total cumulative dose. There are no cases in patients who received infusions for 12 months or less. Mitoxantrone • In placebo-controlled trials of patients with relapsing-remitting multiple sclerosis and a mixed population of relapsing-remitting and secondary progressive multiple sclerosis, ® mitoxantrone (Novantrone ) use was associated with amenorrhea, nausea and vomiting, and urinary tract infections. In the mixed population studies, pooled data found more withdrawals due to adverse events in the mitoxantrone group compared with placebo as well as a non-significant decrease in left ventricular ejection fraction below 50%. Subgroup analysis suggested that higher cumulative doses of mitoxantrone were potentially associated with greater risk of asymptomatic left ventricular ejection fraction <50%, although this failed to reach statistical significance (P=0. One small study (N=18) found transient reduction of left ventricular ejection fraction in 11% when monitored more frequently, but larger trials are needed to determine the validity of this finding as well as the long-term clinical significance. A meta- analysis that included 1620 patients found the overall rate of t-AL to be very low overall (0. Detailed Assessment Beta interferon Three head-to-head trials (N=1166) comparing the interferons in patients with relapsing- 40, 42, 44 remitting multiple sclerosis reported adverse events. Additional data was obtained from placebo-controlled trials (5 placebo-controlled trials in patients with relapsing-remitting multiple 51-56 sclerosis, 5 placebo-controlled trials in patients with secondary progressive multiple 75-83, 132 85, 87 36 sclerosis, 2 placebo-controlled trials and 1 systematic review in patients with primary progressive multiple sclerosis, and 1 meta-analysis of 6 placebo-controlled trials in chronic progressive multiple sclerosis) and observational studies. Adverse events were considered typical in all of the trials, with flu-like syndrome and injection site reactions being common. However, across the studies and types of beta interferons, the ranges were wide even within studies of the same beta interferon. For example, in the 5 trials of patients with secondary progressive multiple sclerosis, the range of flu-like syndrome was ® 37% with 22 µg of interferon beta-1a SC (Rebif ) to 70% with interferon beta-1a IM ® 74-83 (Avonex ). Clearly dosing, definition, and ascertainment varied among the studies. In this Disease-modifying drugs for multiple sclerosis Page 58 of 120 Final Report Update 1 Drug Effectiveness Review Project analysis, we have pooled only to the same dose and dosing schedule of interferon beta-1a SC ® (Rebif ). In the head-to-head trials comparing the beta interferon products, adverse events were not 41 well reported, with 2 of the 5 trials not reporting adverse events. The dose of interferon beta-1a ® SC (Rebif ) was 22 µg weekly in the Koch-Henrisksen study and they only reported combined incidence for a few selected adverse events. Withdrawal or early discontinuation due to an adverse event or any other reason was not found to be different between this low dose of ® ® interferon beta-1a SC (Rebif ) and interferon beta-1b (Betaseron ) 250 µg.