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By A. Seruk. Portland State University.

Considerable differences exist between the methods (Coste 1996) and to change from one method to another is generally not advisable generic prandin 2mg otc. Different subtypes are also detected with varying success according to the method employed (Parekh 1999 purchase prandin 1mg line, Alvarez 2015 purchase prandin 0.5mg with visa, Ndiaye, 2015). One should be particularly cautious in patients from Africa and Asia with non-B subtypes in whom the viral load at first presentation can be unexpect- edly low. In such cases, use of a different assay may actually be indicated. However, newer versions with improved primers and probes are probably superior in measur- ing even unusual HIV subtypes with adequate sensitivity. All assays have a linear dynamic range, outside of which precise numbers are not so reliable. The following rule applies: use one method, one laboratory. The laboratory should be experienced and routinely perform a sufficiently large number of tests. Pre-analytical aspects concerning specimen collection, transport and storage should be taken into account to ensure correct viral load measurement. In particular, it should be noted that for obtaining plasma whole blood should be centrifuged within an adequate time interval (optimally within 24 hours). It is recommended to contact the laboratory ahead of time on these issues. Apparent low-level HIV RNA viraemia can be related to long sample processing time (Portman 2012). Viral load measurement is also vulnerable to contamination. If other examinations such as CD4 T cell count is done in the same lab, it is recommended to send a sep- arated EDTA tube. One study showed a 5- to 160-fold elevated viral load during active tuberculosis (Goletti 1996). Viral load can also increase significantly during syphilis and declines after successful treatment (Buchacz 2004, Kofoed 2006, Palacios 2007). In a large retrospective study, 26% of transient viremia in patients on ART were caused by intercurrent infections (Easterbrook 2002). In these situations, deter- mining the viral load does not make much sense. As the peak occurs one to three weeks after immunization, routine measurements of viral load should be avoided within four weeks of immunization. It should be noted that not every increase is indicative of virologic treatment failure and resistance. Slight transient increases in viral load, or blips, are usually of no consequence, as numerous studies in the last few years have shown (see chapter on Goals and Principles of Therapy). The possibility of mixing up samples always has to be considered. Unusually implausi- ble results should be double-checked with the laboratory, and if no cause is found there, they need to be monitored – people make mistakes. Should there be any doubt on an individual result; the lab should be asked to repeat the measurement from the same blood sample. Viral kinetics on ART The introduction of viral load measurement in 1996-1997 fundamentally changed HIV therapy. The breakthrough studies by David Ho and his group showed that HIV infection has significant in vivo dynamics (Ho 1995, Perelson 1996). The changes in viral load on antiretroviral therapy clearly reflect the dynamics of the process of viral production and elimination. The concentration of HIV-1 in plasma is usually reduced by 99% as early as two weeks after the initiation of ART (Perelson 1997). In one large cohort, the viral load in 84% of patients was already below 1000 copies/ml after four weeks. The decrease in viral load follows biphasic kinetics. The higher the viral load at initiation of therapy, the longer it takes to drop below the level of detection. In one study, the range was between 15 days with a baseline viral load of 1000 and 113 days with a baseline of 1 million viral copies/ml (Rizzardi 2000). The following figure shows a typical biphasic decrease in viral load after initial high levels. Monitoring 249 Figure 1: Viral load kinetics during the first months on first-line ART. The grey values derive from 10 patients who achieved a sustained virological suppression, the black values from 3 patients in which resistance mutations occurred during primary therapy (all 3 had NNRTI-based regimens) Numerous studies have focused on whether durable treatment success can be predicted early (Thiebaut 2000, Demeter 2001, Kitchen 2001, Lepri 2001). In a study on 124 patients, a decrease of less than 0. According to another prospective study, it is possible to predict virologic response at 48 weeks even after 7 days (Haubrich 2011). However, this has little clinical relevance, and in our opinion it is pointless to start measurement of viral load only one or two weeks after initiation of therapy. Many studies have evaluated the question whether long-term virological success can be predicted at early phases (Thibaut 2000, Demeter, Kitchen 2011, Lepri 2001).

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The dosing of the drug was 15 mg subcutaneously twice daily prandin 0.5 mg mastercard, a dose that is higher than currently used (20 mg subcutaneously daily) 1 mg prandin overnight delivery. The mean baseline Expanded Disability Status Scale was slightly higher in the glatiramer acetate group (5 discount 1mg prandin visa. Comparing time to sustained progression curves (the primary outcome) while the glatiramer acetate curve showed slower progression, no significant difference was found between the groups over a 2-year period. This study did not conduct a sample size calculation, and with 106 patients may have been underpowered to show a difference of this magnitude. Further, subgroup analyses indicated that patients enrolled at the 2 centers responded differently while on study, and that overall patient disease activity differed on trial compared with the pre-trial assessment period. Analysis of secondary outcomes indicated that statistically significant differences in proportions with progression (defined as an increase on Expanded Disability Status Scale of ≥ 1 if baseline ≥ 5, and 1. The authors also explored a definition of progression of an increase of only 0. Using this definition, the probability of progression was significantly lower with glatiramer acetate compared with placebo only at the 24-month time point (44. Do disease-modifying treatments for multiple sclerosis differ in their effects on the development or recurrence of interferon beta neutralizing antibodies? Summary of the Evidence ® • Interferon beta-1a IM (Avonex ) appeared to have the lowest immunogenicity, with rates of development of neutralizing antibodies of 2% to 8. Disease-modifying drugs for multiple sclerosis Page 46 of 120 Final Report Update 1 Drug Effectiveness Review Project Detailed Assessment Neutralizing antibodies are known to develop in some patients taking beta interferons, potentially interfering with effectiveness. Two systematic reviews summarized the current state of understanding about the impact 98, 99 of these antibodies on relapse and disease progression, and how the products differ. There were several factors that can impact the prevalence of such antibodies, including assay method (varying sensitivity/specificity), dose (conflicting evidence), host cell source (Escherichia coli more antigenic than mammalian source), definition of positive status, and route of administration (subcutaneous more antigenic than intramuscular). Because there is no standardized universal assay, comparisons across studies of the beta interferons is fraught with uncertainty. It appears that the rate of antibody development occurs earlier and in greater frequency with interferon ® beta-1b SC (Betaseron ), appearing as early as 3 months into treatment in approximately 30% to 99 40% of patients. Evidence reported in the Namaka review indicated that antibodies occur ® somewhat later (9 months) with interferon beta-1a SC (Rebif ), with rates as low as 12% and as ® high as 46% (see Table 18). Interferon beta-1a IM (Avonex ) appeared to have the lowest immunogenicity with rates of 2% to 8. Importantly, 40% to 50% of antibody-positive patients will become antibody-negative over time, while small numbers of patients will become antibody-positive into the second year of treatment. Comparison of neutralizing antibodies in beta interferon products Avonex Betaseron Rebif Percent developing neutralizing 2% to 6% 30% to 40% 12% to 25% antibodies First 3-6 months, can Time to appear First 9-15 months First 9-15 months occur up to month 18 Data from 9 comparative observational studies reporting the presence of neutralizing 100-108 antibodies in patients taking beta interferons are shown in Table 19 below. The proportion ® of patients developing antibodies was lower for interferon beta-1a IM (Avonex ), 0% to 14%, ® compared with 11% to 44% with interferon beta-1a SC (Rebif ) and 15% to 44% with interferon ® beta-1b SC (Betaseron ), consistent with findings from the Namaka systematic review. The usefulness of these studies in making comparisons across drugs was limited because most did not study patients on therapy for more than 2 years. Disease-modifying drugs for multiple sclerosis Page 47 of 120 Final Report Update 1 Drug Effectiveness Review Project Table 19. Proportion of patients testing neutralizing antibody-positive after beta interferon therapy reported in comparative observational studies Association of clinical Author, Duration of outcomes with neutralizing ® ® ® year treatment Avonex Betaseron Rebif antibody status More relapses in neutralizing 16/131 Boz, 2007 >3 years 0/12 (0%) 18/119 (15%) antibody-positive patients in (12. Relapse rates higher in Farrell, 24/292 neutralizing antibody-positive >3 years 4/242 (6%) 11/115 (28%) 2008 (30%) groups, risk greater in those with higher titres Median 26 No significant association Dubois, 10/23 months, range 0/18 (0%) 12/32 (38%) between antibody status and 2006 (44%) 2-85 months outcomes. Kivisakk, No effect of neutralizing 1-46 months 1/20 (5%) 21/48 (44%) 2000 antibodies on clinical outcome Koch- 21,963 Effect of neutralizing antibody N=417 N=892 Henriksen months of status on relapses did not differ 33. They are not discussed in detail here because 80, 107, they provided no additional evidence beyond the Namaka and Goodin systematic reviews. What is the evidence that interferon beta neutralizing antibody status has an impact on clinical outcomes (relapse and disease progression) in patients with multiple sclerosis? Summary of the Evidence ® ® • Evidence for interferon beta-1b SC (Betaseron ) and interferon beta-1a SC (Rebif ) indicated that consistent positive neutralizing antibody status with high titer adversely affected the impact of these drugs on relapse rates, by one-half to two-thirds, during longer periods of follow-up. Detailed Assessment The duration of many studies was not adequate to assess the impact of antibody status on progression clearly. Namaka et al found that in the first 2 years of treatment a difference in outcome based on antibody status could not be identified, but that relapse rates were lower in years 3 and 4 among patients who were antibody-positive (Table 20). The review by Goodin et 98 al also found that relapse rates were affected by positive neutralizing antibody status of high titer only in studies of 2 years or longer in duration. The evidence for the impact on disease progression was less compelling, with only 2 of 8 studies showing a significant increase in progression among those with neutralizing antibodies. Duration of treatment and clinical impact of antibody status Interferon β-1b SC Interferon β-1a SC ® ® ® Duration (Betaseron ) (Rebif ) Interferon β-1a IM (Avonex ) nd “correlation not 1. Two trials published subsequent to the Goodin and Namaka systematic reviews reported rates of interferon beta neutralizing antibodies occurring in enrolled patients. Most of these may not have been of sufficient duration to show clinical effects of antibody development, however. In the EVIDENCE trial, which compared interferon high-dose, high-frequency interferon beta-1a ® ® (Rebif ) 44 mcg to low-dose interferon beta-1a IM (Avonex ) 30 mcg over 2 years, neutralizing ® antibodies were detected at least once in 26% of patients receiving high-dose Rebif and in 3% ® of those receiving low dose Avonex (P<0. Neutralizing antibodies developed earlier with high-dose treatment (58% by week 24, compared with 14% in the low-dose group). Relapse rates 45 were similar in antibody-positive and antibody-negative patients. The proportion of patients developing neutralizing antibodies was reported in the ® REGARD study of interferon beta-1a (Rebif ). The rate was 60/138 (16%) at 24 weeks, 93/355 Disease-modifying drugs for multiple sclerosis Page 49 of 120 Final Report Update 1 Drug Effectiveness Review Project (26%) at 48 weeks, 91/319 (29%) at 72 weeks, and 102/374 (27%) at 96 weeks or last observation carried forward. Neutralizing antibodies had no effect on clinical efficacy: there was no difference in time to first relapse for those positive at any time and those negative (hazard ratio, 1. Although there was an association between neutralizing antibody status and clinical outcome shown in several studies, none found the detrimental effect of positive antibody status to be greater with one of the beta interferons than another.

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G-CSF (granulocyte colony-stimulating factor) is available as filgastrim (Neupogen) order prandin 2mg line, lenogastrim (Granocyte) and most recently as less expensive biosimilars (in Europe) discount prandin 2mg with amex. It is also licensed for permanent neutropenia in advanced HIV infection to avoid bacterial infection generic 0.5mg prandin mastercard. In a randomized study with 258 HIV-infected patients with CD4 T cells under 200/µl, the rate of severe neutropenia was 2% versus 22% in the control group after 24 weeks (Kuritzkes 1998). Incidence of bacterial infection was reduced by 31% and the number of inpatient days dropped by 45%. ART 2017/2018: The horizon and beyond 139 were seen. Patients with CMV retinitis showed a large survival benefit on G-CSF (Davidson 2002). Although severe neutropenia has become rare on ART, G-CSF can be useful, especially in chemotherapy, with interferon or other myelo-suppressive drugs such as valgancyclovir. GM-CSF (granulocyte macrophage colony-stimulating factor) is available as molgramostim (Leucomax) or sargramostim (Prokine). Three double-blind, randomized studies showed a slight effect on viral load (Angel 2000, Skowron 1999, Brites 2000). However, in one study in patients with uncontrolled infection, there was a slight increase of viremia (Jacobsen 2003). GM-CSF seems to prevent signifi- cant loss of CD4 T cells during treatment interruptions (Fagard 2003). Given the side effects and significant cost of GM-CSF, it cannot be recommended outside clinical studies. Hydroxyurea (HU, Litalir) is an old chemotherapeutic agent with relatively low toxicity still being used today in hematology (mostly in chronic myelogenous leukemia). It inhibits DNA synthesis via the ribonucleotide reductase, and leads to an intracellular shortage of deoxynucleotide triphosphates. A synergistic effect on HIV replication in combination with ddI was demonstrated in 1994 (Lori 1994). A Swiss study, in which 144 patients were treated with hydroxyurea (HU) or placebo plus d4T+ddI, attracted attention in 1998 (Rutschmann 1998). After 12 weeks, 54% (versus 28% in the placebo group) demonstrated a viral load below 200 copies/ml. Was this the discovery of a new cheaper option for HIV treatment? Hydroxyurea became even more fashionable after publication of the first “Berlin Patient”, a patient who had been treated with hydroxyurea in addition to indinavir and ddI during acute infection, had stopped all therapy after a few months and subsequently showed no detectable plasma viremia (Lisziewicz 1999). Several small studies from the US and Argentina seemed to confirm these positive results. Many treating physicians added the drug to ART and many started to dream of a cheap combination of ddI+HU for Africa. In particular, the combination of HU with ddI and d4T turned out to be particularly toxic: severe polyneuropathy (Moore 2000) and fatal pancreatitis were reported (Havlir 2001). Three randomized studies failed to show any effect, except for high rates of toxicity (Blanckenberg 2004, Stebbing 2004, Swindels 2005). Even in patients with acute HIV infection there was no effect. Thus, more Berlin patients could not be “reproduced” (Zala 2002). Hydroxyurea should not be used in antiretroviral therapy. Interferons have an antiretroviral effect that has been known for years (Mildvan 1996). The antiviral effect of 3 million IU daily or with pegylated interferon weekly is about 0. Higher dosing may increase this effect (Hatzakis 2001). We have seen patients coinfected with HIV/HCV, who achieved an undetectable HIV RNA during hepatitis C therapy with interferon and ribavirin only. However, an in-depth investigation of the antiviral activity of interferon was not conducted, because of the subcutaneous delivery route and its not insignificant side effects. Recently, interferons seem to be experiencing a come- back, as they may acheive importance as an immune modulator and play a role in eradication (Papasavvas 2012, Mexas 2012). In one trial, 9 out of 20 patients who received pegylated interferon and interrupted ART, showed viral load below 400 copies/ml after 12 weeks of IFN monotherapy (Azzoni 2013). Interleukin-2 (IL-2, aldesleukin, Proleukin) is a cytokine produced by activated T cells that induces proliferation and cytokine production in T cells, B cells and NK cells. It has been employed in oncology for years and is now usually administered 140 ART subcutaneously. The most important effect of IL-2 in HIV medicine is the increase in CD4 and CD8 T cells, which may be quite impressive in individual cases. CD45RO memory cells initially increase, followed by naïve CD45RA T cells (Chun 1999, Carcelain 2003). This effect is mainly due to a reduced T cell turnover (Kovacz 2005, Sereti 2005, Vento 2006). The question of whether the CD4 T cells generated by IL-2 would lead to clinical benefit, was answered by two large randomized studies, ESPRIT and SILCAAT, in 2009 (Abrams 2009). In the ESPRIT study, 4,131 patients with at least 300 CD4 T cells/µl were treated with and without IL-2 in addition to ART. SILCAAT had a similar concept, but enrolled 1695 patients with 50-299 CD4 T cells/µl. Although supplementation of ART with IL-2 resulted in a statistically significant increase in CD4 T cell count (ESPRIT: +160, SILCAAT: +59 CD4 T cells/µl), it did not lead to a clinical benefit.

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