HIV Medicine - part 4 pot

250 ART 2006 29. Katlama C, Carvalho MI, Cooper D, et al. TMC 114/r out performs investigator selected PI(s) in three class-experienced patients: week 24 primary analysis of POWER 1 (TMC 114-C213). Abstract WeOaLB0102, 3rd IAS 2005, Rio de Janeiro. 30. Katlama C, Dominguez S, Duvivier C, et al. Benefits of treatment interruption in patients with multiple therapy failures, CD4 cells <200 /mm3 and HIV RNA >50 000 cp/ml. Abstract 5887, XIV Int AIDS Conf 2002, Barcelona. 31. Katlama C, Dominguez S, Gourlain K, et al. Benefit of treatment interruption in HIV-infected patients with multiple therapeutic failures: a randomized controlled trial (ANRS 097). AIDS 2004, 18:217-26. http://amedeo.com/p2.php?id=15075539&s=hiv 32. Kempf DJ, Isaacson JD, King MS, et al. Identification of genotypic changes in HIV protease that corre- late with reduced susceptibility to the protease inhibitor lopinavir among viral isolates from protease in- hibitor-experienced patients. J Virol 2001, 75:7462-9. http://amedeo.com/lit.php?id=11462018 33. Khanlou H, Farthing C. Favorable interaction between atazanavir and fosamprenavir with and without ritonavir in the treatment of HIV-infected patients. Abstract P288, 7th Int Congress Drug Ther HIV Inf 2004, Glasgow. 34. Khanlou H, Graham E, Farthing C. Drug interactions between amprenavir and lopinavir/ritonavir in salvage therapy. AIDS 2002, 16:797-798. 35. Klein C, Bertz R, Ashbrenner E, et al. Assessment of the multiple-dose pharmacokinetic interaction of lopinavir/ritonavir with nelfinavir. Abstract 536, 10th CROI 2003, Boston. 36. la Porte CJ, Schippers EF, van der Ende ME, et al. Pharmacokinetics of once-daily lopinavir/ritonavir and the influence of dose modifications. AIDS 2005, 19:1105-7. http://amedeo.com/lit.php?id=15958844 37. Lalezari JP, Henry K, O'Hearn M, et al. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N Engl J Med 2003, 348:2175-85. http://amedeo.com/lit.php?id=12637625 38. Langmann P, Zilly M, Winzer R, et al. Efficacy and safety of ATV in combination with LPV/r. Abstract 56, 6th IWCPHT 2005, Quebec. 39. Lawrence J, Mayers DL, Hullsiek KH, et al. Structured treatment interruption in patients with multidrug- resistant HIV. N Engl J Med 2003, 349:837-46. http://amedeo.com/lit.php?id=12944569 40. Lazzarin A, Clotet B, Cooper D, et al. Efficacy of enfuvirtide in patients infected with drug-resistant HIV- 1 in Europe and Australia. N Engl J Med 2003; 348:2186-95. http://amedeo.com/lit.php?id=12773645 41. Lazzarin A, Mukwaya G, Clumek N, et al. Tipranavir/ritonavir (TPV/r) demonstrates superior treatment response to lopinavir/r, amprenavir/r or saquinavir/r in PI-experienced patients from the TPV RESIST-1 and RESIST-2 trials. Abstract WePe6.3C07, 3rd IAS 2005, Rio de Janeiro. 42. Ledergerber B, Lundgren JD, Walker AS, et al. Predictors of trend in CD4-positive T-cell count and mortality among HIV-1-infected individuals with virological failure to all three antiretroviral-drug classes. Lancet 2004, 364:51-62. http://amedeo.com/lit.php?id=15234856 43. Leen CS et al. Pharmacokinetics of indinavir when co-administered with tipranavir/ritonavir. Abstract 299, 7th Int Congress Drug Ther HIV Inf 2004, Glasgow. 44. Legrand FA, Abadi J, Jordan KA, et al. Partial treatment interruption of protease inhibitors augments HIV-specific immune responses in vertically infected pediatric patients. AIDS 2005, 19:1575-1585. 45. Lohse N, Obel N, Kronborg G, et al. Declining risk of triple-class antiretroviral drug failure in Danish HIV-infected individuals. AIDS 2005, 19:815-22. http://amedeo.com/lit.php?id=15867496 46. Lucas GM, Gallant JE, Moore RD. Relationship between drug resistance and HIV-1 disease progres- sion or death in patients undergoing resistance testing. AIDS 2004, 18:1539-48. http://amedeo.com/lit.php?id=15238772 47. Masquelier B, Breilh D, Neau D, et al. HIV-1 genotypic and pharmacokinetic determinants of the vi- rological response to lopinavir-ritonavir-containing therapy in protease inhibitor-experienced patients. Antimicrob Agents Chemother 2002, 46:2926-32. http://amedeo.com/lit.php?id=12183249 48. Mauss S Schmutz G, Kuschak D. Unfavourable interaction of amprenavir and lopinavir in combination with ritonavir? AIDS 2002, 16:296-297. 49. Mauss S, Scholten S, Wolf E, et al. A prospective, controlled study assessing the effect of lopinavir on amprenavir concentrations boosted by ritonavir. HIV Med 2004, 5:15-7. 50. Mellors J, Bennett FVK, Hellmann NS, et al. Efavirenz hypersusceptibility improves virologic response to multidrug salvage regimens in ACTG 398. Abstract 45, 9 th CROI 2002, Seattle, USA. http://www.retroconference.org/2002/Abstract/12985.htm 51. Miller V, Cozzi-Lepri A, Hertogs K, et al. HIV drug susceptibility and treatment response to mega- HAART regimen in patients from the Frankfurt HIV cohort. Antivir Ther 2000, 5:49-55. http://amedeo.com/lit.php?id=10846593 252 ART 2006 73. Zaccarelli M, Tozzi V, Lorenzini P, et al. Multiple drug class-wide resistance associated with poorer survival after treatment failure in a cohort of HIV-infected patients. AIDS 2005, 19:1081-9. http://amedeo.com/lit.php?id=15958840 74. Zilly M, Winzer R, Nolte C, et al. Double PI boosting with atazanavir and fos-amprenavir: favourable pharmacokinetics. Abstract 93, 6th Int Workshop Clin Pharmacol HIV Therapy 2005, Quebec. 10. When to stop HAART 253 10. When to stop HAART A current review of treatment interruption Christian Hoffmann Hardly a topic in the field of HIV medicine has evoked more heated discussion in the last years than treatment interruption. However, in the discussion over possible risks (AIDS, resistance) or advantages (reduction of toxicity and costs), many is- sues are confused. It is not only between structured treatment interruptions (STIs), which are made with the knowledge of the treating doctor, and unstructured “drug holidays” that a distinction needs to be drawn. But, the reasons for the interruption of treatment should also be made clear. The reasons can differ greatly. • At the patient’s request • To improve compliance and psyche (“life sentence” removed) • To reduce long-term toxicity • For immunological reasons • As a salvage strategy Many treatment interruptions occur without the clinician’s knowledge. For this rea- son alone, treatment interruptions are an important constituent of antiretroviral therapies, whether, as a clinician, one approves of them or not. To oppose them means to disregard the realities of treatment. The following chapter provides an overview of the current knowledge in this area. It is limited to patients with chronic HIV infection; (for recommendations on acutely infected patients see the chapter on “Acute HIV Infection”). Viral load and CD4+ T-cells during treatment interruption Almost all patients who stop treatment experience a “rebound” in viral load within a few weeks, even patients in whom this has been undetectable for several years (Davey 1999, Chun 2000). Viral load is usually detectable again within 10-20 days (Davey 1999, Harrigan 1999, Garcia 1999), and its doubling time in the blood is around 1.6 – 2.0 days. The viral load in compartments such as the CNS, as well as the semen and vaginal fluids, changes in parallel to that in the plasma (Garcia 1999, Neumann 1999). The patients should therefore be informed about the higher risk of transmitting HIV. Frequently, an initial overshooting rebound is observed (De Jong 1997, Birk 2001), and only after a few weeks does the viral load settle to its original, pre-treatment level (Hatano 2000). The rebounding virus evidently does not originate from latent reservoirs; other cell populations must exist, from which these new viruses can be produced so quickly (Chun 2000, Ho 2000, Imamichi 2001). Treatment interruptions can have serious immunological consequences. Often, CD4+ T-cell counts drop within a short time to pre-treatment levels. The ground that has been gained on HAART is rapidly lost again. The drop is biphasic, and the interval strongest in the first few months (Fagard 2005, Wit 2005, Skiest 2006). 254 ART 2006 CD4+ T-cell losses vary greatly between patients but may reach 200 or 300/µl within a few weeks. The higher and faster the CD4+ T-cells increased on HAART, the more rapid their decline (Tebas 2002). The CD4 nadir is also important. The lower it was, the more rapidly the cell count drops again (Maggiolo 2004, Skiest 2006). Age is also important – the older the patient, the more extensive the immu- nological deterioration. The loss of CD4+ T-cells during an interruption may not be regained as quickly. In a prospective study, we saw a significant disadvantage for patients undergoing treatment interruptions. After a follow up of 18 months, CD4+ T-cells were more than 120/µl less in these patients than in matched patients who had not interrupted treatment (Wolf 2005). The risks: resistance, clinical problems, AIDS Viral resistance always have to be anticipated whenever there is viral replication in the presence of suboptimal drug levels, and thereby resistant mutants gain a selec- tive advantage over the wild-type virus. As a result, there are concerns that resis- tances could develop both during the washout phase of medication (increasing viral replication with insufficient plasma levels) and on re-initiation of treatment (contin- ued replication despite sufficient plasma levels). However, in the case of single treatment interruptions, the probability of this does not appear to be particularly high, as shown in 1999 by the small French COMET Study, one of the first studies on treatment interruption (Neumann 1999). But, there is no certainty as to whether interruptions might not eventually lead to development of resistant isolates, which merely require more time until they are able to dominate the wild-type. Mathematical models show that this risk – at least theoretically – is not low, especially if viral load rises to high levels (Dorman 2000, Bonhoeffer 2000). The risk of resistance is probably higher for repeated treatment interruptions. In several studies, these have led particularly to NNRTI- or 3TC-resistance (Martinez- Picado 2002, Schweighardt 2002, Ruiz 2005). The risk seems particularly high for strategies involving stopping and starting of HAART at fixed intervals (see below). Table 10.1 describes the example of a patient who was clinically well and who in- terrupted treatment. It was probably the repeated stopping and starting of HAART that ultimately led to resistance in this case. The sharp increase in viral load that may often occur can present as a retroviral syndrome. The symptoms are similar to acute HIV infection, with lymphadenopa- thy, fever, asthenia and malaise (Colven 2000, Kilby 2000, Zeller 2001, Ruiz 2004). Thrombocytopenia has also been described during interruptions (Ananworanich 2003). The blood count needs to be monitored, especially in patients with a previ- ous history of thrombocytopenia. Finally, attention should also be paid to patients who are co-infected with hepatitis B virus. If the HBV treatment with 3TC, FTC or tenofovir is interrupted, HBV rebound can result in fulminant and life-threatening hepatitis (Sellier 2004). It is therefore advisable to look after these patients very carefully and monitor the liver enzymes at least every two weeks. 10. When to stop HAART 255 Table 10.1: Example of the development of resistance due to repeated treatment interrup- tions* Date HAART/comments CD4 + T-cells Viral load Jun 97 AZT+3TC+SQV 288 67,000 Oct 99 HAART stopped, patient feeling well 540 < 50 Dec 99 Diagnosis of autoimmune hyperthyroidism 400 63,000 Jan 00 AZT+3TC+NVP (+ carbimazole) 260 74,000 Feb 00 Diagnosis of anemia (Hb 7.3 g/dl) HAART stopped again 347 1,500 Mar 00 d4T+3TC+NVP (+ carbimazole) Apr 00 Resistance mutations K103N, M184V 360 2,400 *During the first treatment interruption the patient developed autoimmune hyperthyroidism, the treatment of which led to anemia after re-initiation of HAART, so that HAART was interrupted again. As a result, resistance developed against NNRTIs and 3TC. Autoimmune phenomena in the context of treatment interruption as seen in this patient have not previously been described. The risk of AIDS seems to be low for single interruptions provided the immune defect is only moderate. In the Swiss Cohort, the risk of progression was not in- creased (Taffe 2002). In 133 patients who interrupted treatment, we observed no increased risk of AIDS after 24 months, compared to 262 matched controls (Wolf 2005). However, almost all patients in this study were immunologically stable throughout. The risk is probably higher in patients with severe immunodeficiency (Deeks 2001, Lawrence 2003). The CPRC064 Study in which 270 patients with MDR viruses and mostly distinct immunodeficiency (median 144 CD4+ T-cells/µl) were randomized before a salvage regimen either to a four-month treatment inter- ruption or not, was stopped because of a high risk of progression. In comparison with the control group, a significantly higher number of AIDS illnesses (17 versus 5) occurred in the group interrupting therapy. In a multivariate analysis, two factors were predictive for death or progression: treatment interruption and the CD4+ T- cell count at the time of interruption. The risk increased by 1.4 with every drop of 50 CD4+ T-cells demonstrating that severely immunocompromised patients are particularly at risk of developing AIDS during long treatment interruptions of sev- eral months. Treatment interruptions should be avoided in such patients. Newer data from the SMART Study, however, show that even with higher CD4+ T-cells, treatment interruptions can lead to the development of AIDS (see below). STI at the patient’s wish, and for reduction of toxicity Interruption of therapy can have psychological advantages (Tuldra 2001). Quality of life improves (Moreno 2003), and many patients are relieved of the burden of continuous, “lifelong” therapy. Clinicians should take the wish for treatment inter- ruption seriously. Presumably most patients expressing such a wish will interrupt sooner or later anyway; so the interruption may as well be structured and controlled. However, the psychological benefit of treatment interruption has not been con- firmed by studies – in fact it is striking how few studies have been based on this theme. 256 ART 2006 Increased transaminases or lipid levels drop quite rapidly after stopping treatment (Hatano 2000, Wolf 2005). It is still not clear whether this is relevant in reducing the risk of cardiovascular disease. In SMART, the risk of cardiovascular and meta- bolic complications during STIs was actually increased (El Sadr 2006, see below). At present, it seems at least questionable that, through solitary or repeated interrup- tions, so much HAART can be saved as to improve the cardiovascular risk profile. What about lipodystrophy and mitochondrial toxicity? At least two studies have shown that, after a few months, mitochondrial DNA can regenerate itself during a treatment break (Cote 2002, Mussini 2005). In contrast, another study showed no effect (Negredo 2006). Whether or not a clinically manifested lipodystrophy im- proves, remains to be proven. At least short treatment interruptions have not had any effect on morphological changes (Hatano 2000). Resolution of lipodystrophy even after longer interruptions is by no means certain; we have a patient who was treated during seroconversion and developed a “buffalo hump” after one and a half years, which has not resolved even after almost five years of treatment interruption. Summary: although a treatment interruption, is theoretically substantiated to deal with the worries of long-term toxicity on HAART, a convincing argument has not been provided by the data so far. STI – for immunological reasons Hardly any patient has become as famous as the acutely infected homosexual man treated in a Berlin private practice a few years ago who, with a viral load of ap- proximately 80,000 copies/ml, began a HAART regimen consisting of didanosine, indinavir and hydroxyurea. The virus rapidly became undetectable. After several problems – and two short treatment interruptions – HAART was completely stopped after 176 days. Surprisingly, even without drugs, plasma viremia has re- mained below the level of detection for more than five years. Although virus was still detectable in lymph nodes, thus excluding eradication, the immune system in this case – referred to as the Berlin Patient among experts in the field (Lisziewicz 1999) – was obviously capable of durable control of infection. But why? Was it the early initiation of therapy, the hydroxyurea, or the treatment interruptions? To be honest, it must be admitted that no one knows the answer, even today. There may be a completely different explanation: it is possible that certain host factors in this patients that have not yet been investigated could influence the course of disease – completely independently of HAART, STI or hydroxyurea. Nevertheless, STI has been extensively investigated in acutely infected patients (see chapter “Acute HIV infection”). Attempts to improve HIV-specific immune responses with treatment interruptions in chronically infected patients have been unsuccessful. The theory of “endogenous vaccination” seems plausible: transient increases in viral load could strengthen HIV-specific immune responses, which decline with increasing viral suppression on HAART. In several pilot studies from 2000/2001, successive interruptions seemed to indeed prolong the time to viral rebound or decrease the rate of rebound, and, in parallel, there were measurable improvements in HIV-specific CD4+ or CD8+ T-cell im- mune responses (Haslett 2000, Garcia 2001, Lori 2000, Ortiz 1999, Papasavvas 10. When to stop HAART 257 2000, Ruiz 2000). However, almost none of these studies included more than 2- 6 patients, and a control group was usually missing. Was this wishful thinking? STI was finally “put to the test” in the Spanish-Swiss SSITT Study (Oxenius 2002, Fagard 2003): 133 patients were monitored throughout four ten-week treatment cycles, each consisting of eight weeks HAART and two weeks of treatment inter- ruption. After this, HAART was permanently interrupted. Treatment success – de- fined as a viral load below 5,000 copies/ml without HAART after 52 weeks – oc- curred in 21/99 patients. However, 5/21 patients had a low viral load even before the initiation of HAART. Most importantly, none of the 32 patients with a pre- HAART viral load above 60,000 copies/ml achieved a viral load of less than 5,000 copies/ml. The viral load set point is lowered in only a few patients, usually those with low initial viral load, despite repeated STIs. In contrast to acute infec- tion, improvement of HIV-specific immune response seems unlikely in the setting of chronic HIV infection. SSIT clearly showed that treatment interruptions on im- munological grounds alone are not justified and are dangerous. In addition, approaches with immunomodulatory drugs, such as hydroxyurea (Foli 2004), mycophenolat (Garcia 2004) or steroids (Ulmer 2005), exist to lengthen the period of STIs. These approaches, whose benefits anyway seem questionable, are still in the experimental phases and not justified outside studies. STI as a salvage strategy for MDR viruses In most patients with MDR viruses, treatment interruption leads to a gradual shift back to the wild-type virus and a loss of resistance. Therefore, resistance testing during treatment interruption is often of little use since mutations disappear from the blood as early as two weeks after treatment interruption (Devereux 1999). In modestly immunosuppressed patients, this shift is observed more frequently and faster. In more advanced stages of disease and with a longer duration of treatment, it lasts longer (Miller 2000, Izopet 2000), and sometimes after a longer interruption of therapy, no shift can be seen (Halfon 2005). Providing the shift is visible: PI mutations are the first to disappear, while NNRTI mutations are more protracted because they hardly affect the viral fitness (Deeks 2001, Birk 2001). It is assumed that the wild type merely dominates the resistant mutants. Special PCR methods are still able to detect low quantities of resistant viruses during STI (Izopet 2000), and after treatment is restarted, resistance mutations rapidly dominate again (Delaugerre 2001). Only a few cases have been described in which resistance mutations were apparently flushed out completely. One such patient, from Germany, has been de- scribed (Walter 2002), who was not able to attain sufficient viral suppression de- spite intensified HAART, and who then interrupted treatment. During the following seven months of treatment interruption, there was a gradual reversion to the wild- type virus, and after re-starting HAART (which, according to previous resistance testing, should have had no effect) the viral load has now been successfully sup- pressed for several years. Can patients with multi-resistant viruses improve the effect of the salvage regimen, if they have had a previous interruption of treatment? At least two studies to date have shown that the shift resulting from treatment interruptions can be beneficial for salvage strategies. In the Frankfurt Cohort, a shift was associated with improved response to the salvage regimen (Miller 2000). In the GIGHAART Study, there was 258 ART 2006 still evidence of antiviral efficacy after one year in patients who had interrupted treatment before starting a salvage regimen (Katlama 2004). However, this data is in contrast to that of numerous other studies in which an increased risk of AIDS was seen during treatment interruptions (Lawrence 2003, Ruiz 2003, see above). At the end of 2005, a further work, the Reserve Study, was published, which brought the concept of STI in multiresistance under more scrutiny than before (Ghosn 2005). A total of 23 patients with MDR viruses, on long-term therapy and severely immunosuppressed, interrupted their HAART until at least two drugs became ef- fective again according to genotypic resistance tests. The interval lasted 24 weeks on average, after which an intensive salvage regimen was started (usually at least 6 drugs). The results were sobering: nothing changed during the interruption. After 12 weeks on the salvage regimen, the viral load was practically unchanged in compari- son to the baseline value. An even more disturbing side effect: in 15/23 (65 %) of the patients, AIDS illnesses occurred, sometimes even after the interruption. Summary: in view of the risk of AIDS and the lack of evidence regarding the bene- fits, treatment interruptions are not justified as salvage strategies outside clinical studies, at least in the severely immunosuppressed. Structured intermittent treatment, fixed intervals In the initial phase following interruption of HAART, the viral load usually contin- ues to be very low. Plasma viremia only reaches pre-treatment levels after about four, sometimes even six weeks. The risk of developing resistance is presumably small at lower levels of viral replication (Bonhoeffer 2000). Does this indicate that ultra-short treatment interruptions could be utilized to reduce drugs, costs and long- term toxicity? In an NIH pilot study on SIT (structured intermittent treatment), 10 chronically in- fected patients with more than 300 CD4+ T-cells/µl and a viral load below 50 copies/ml were switched to a combination of d4T+3TC+indinavir/r. This combi- nation was administered as seven days of treatment and seven days interruption (7- on-7-off) for a period of at least 44 weeks. The result: neither the viral load nor the proviral DNA increased. CD4+ T-cells and HIV-specific immune responses re- mained unchanged, suggesting that the immune system is probably unaffected by such ultra-short breaks in treatment. A significant reduction in lipid levels did, however, occur (Dybul 2001). Some patients experienced several blips (temporary increases in viral load) to above 100 copies/ml. The same group has recently re- ported successful use of the same strategy in eight patients using ddI+3TC+efavirenz. Seven of eight patients have now been followed for more than 60-84 weeks (Dybul 2004). Nevertheless: at this time, it is impossible to predict whether this treatment strategy might result in a higher risk of resistance in the long term. There are still no larger studies, and it has become suspiciously quiet in this area. In addition, patients in the NIH pilot studies were carefully selected, with good immune status and many years of viral suppression. This strategy is probably only applicable to a few patients. A three-armed study from Thailand has already gathered more negative experience with the 7-on-7-off approach (Cardiello 2005). In this study, 19 of 36 patients experienced virological treatment failure within a short period of time, and this treatment arm was consequently stopped prematurely. The main reason for these poor results appears to lie in the fact that the majority of 10. When to stop HAART 259 patients were NRTI-experienced. This means: if nucleoside analogs are unstable, such on-off strategies are problematic. ART only on weekdays? This approach was taken by the FOTO Study (“Five On, Two Off”), in which HAART was only taken from Monday to Friday and stopped at the weekends (i.e. sparing 28 %). This study enrolled patients on a HAART regimen, who had an undetectable viral load for at least three months. After 48 weeks only one of the 17 NNRTI-treated patients had an increase in viral load, al- though 2 of 9 PI-treated patients did (Cohen 2005). The authors speculate that the long half-life of efavirenz (none of the 9 patients on efavirenz demonstrated an in- crease) could be the reason for this difference. Further studies have to be conducted, before such an approach can be recommended. In contrast, longer interruptions, over several weeks, with fixed intermittent treat- ment seem to be unfavorable. Results from a randomized NIH study with fixed in- tervals (each with one month of STI, two months of treatment) were disconcerting (Dybul 2003). The SIT arm contained significantly more patients with virological treatment failure. Resistance mutations developed particularly against NNRTIs and 3TC, so that the study was stopped early. In the Spanish-Swiss SSITT Study (2 weeks STI, 2 months HAART) some resistance was seen (Yerli 2003), likewise in an Italian study (Palmisano 2006). Even though the French WINDOW Study (two months each of STI and therapy) showed no increase in the number of resistances (Marchou 2006), the studies that indicate fixed interruptions as being susceptible to the development of resistances prevail. CD4-driven interruptions: SMART and the consequences Beside fixed intervals, whether short or long, there is another approach, whereby interruptions are individualized and based on CD4+ T-cell count. In other words, in patients with a good CD4 count, HAART is interrupted until the CD4 count drops below an immunological cut-off, and only then is it restarted. Over the last few years, many non-randomized studies with differing cut-off points and very hetero- geneous patient populations came to the conclusion that this approach is safe and allows for a considerable reduction in drug exposure (Moreno 2003, Boschi 2004, Maggiolo 2004, Skiest 2004, Fernandez 2005, Mussini 2005). In the meantime, a few randomized studies compare such CD4-driven intervals with continuous ad- ministration of HAART. The relevant data and results of these studies are given in Table 10.2. It is clear that the results of these randomized studies differ considerably in part. Whilst TIBET, Staccato or ACTG 5170 produced the verdict that CD4-driven inter- ruptions are safe, two other studies, Trivucan and SMART came to other conclu- sions. [...]... increases in CD4 cell counts of HIV- positive persons receiving long-term highly active antiretroviral therapy J Infect Dis 20 04, 190:186 0-8 http://amedeo.com/lit.php?id=1 549 9 544 47 Smith CJ, Staszewski S, Sabin CA, et al Use of viral load measured after 4 weeks of highly active antiretroviral therapy to predict virologic outcome at 24 weeks for HIV- 1-positive individuals J AIDS 20 04, 37:115 5-1 159 http://amedeo.com/lit.php?id=15319675... the CD4+ T-cells, the more frequently patients should be examined Table 11.2: Minimal evaluations per year in stable asymptomatic patients Blood count, LDH, ALT, AST, creatinine, bilirubin, AP, lipase, γGT, glucose Viral load CD4+ T-cells Lipids Physical examination Gynecological examination Fundoscopy if CD4+ T-cells < 200/µl Patient on ART per year 4- 6 x Untreated per year 2 -4 x 4x 2 -4 x 1-2 x 2 -4 x... 4x 2 -4 x 1-2 x 2 -4 x 1x 2 -4 x 2 -4 x 2 -4 x 1x 1-2 x 1x 4x In patients with less than 200 CD4+ T-cells/µl, we usually perform fundoscopies every three to six months to exclude CMV retinitis Close cooperation with an HIVexperienced ophthalmologist is important The better the CD4 cells, the less often fundoscopies are necessary – in our opinion, when CD4+ T-cell counts have nor- 11 Monitoring 275 malized,... et al Emergence of drug-resistant HIV- 1 variants in patients undergoing structured treatment interruptions AIDS 2002, 16:2 34 2-2 344 http://amedeo.com/lit.php?id=1 244 1810 64 Sellier P, Clevenbergh P, Mazeron MC, et al Fatal interruption of a 3TC-containing regimen in a HIVinfected patient due to re-activation of chronic hepatitis B virus infection Scand J Infect Dis 20 04, 36:53 3-5 65 Skiest D, Havlir... CD4+ T cell loss in therapy-naive HIV- patients without antiretroviral therapy Eur J Med Res 2005, 10:10 5-9 72 Walter H, Low P, Harrer T, et al No evidence for persistence of multidrug-resistant viral strains after a 7-month treatment interruption in an HIV- 1-Infected Individual J AIDS 2002, 31:13 7 -4 6 http://amedeo.com/lit.php?id=123 947 91 73 Wit FW, Blanckenberg DH, Brinkman K, et al Safety of long-term... Dis 2003, 188:38 8-9 6 http://amedeo.com/lit.php?id=12870120 20 Dybul M, Nies-Kraske E, Dewar R, et al A proof-of-concept study of short-cycle intermittent antiretroviral therapy with a once-daily regimen of didanosine, lamivudine, and efavirenz for the treatment of chronic HIV infection J Infect Dis 20 04, 189:197 4- 8 2 http://amedeo.com/lit.php?id=15 143 462 21 El-Sadr W, Neaton J Episodic CD4 guided use of... Every HIV patient should have had a CD4+ T-cell measurement within the last six months! Two reference values are generally accepted: above 40 0-5 00 CD4+ T-cells/µl, severe AIDS-related diseases are very rare; below 200 CD4+ T-cells/µl, the risk of AIDS-related morbidity increases significantly with increased duration of immunosuppression However, most AIDSrelated illnesses only occur below 100 CD4+ T-cells/µl... patients with high CD4 cell counts and virologic suppression: results of a prospective, randomized, open-label trial (Window - ANRS 106) Abstract 1 04, 13th CROI 2006, Denver 48 Martinez-Picado J, Morales-Lopetegi K, Wrin T, et al Selection of drug-resistant HIV- 1 mutants in response to repeated structured treatment interruptions AIDS 2002, 16:89 5-9 http://amedeo.com/lit.php?id=1191 949 1 49 Miller V, Sabin... antiretroviral-drug therapy in HIV- infected patients with detectable viremia N Engl J Med 2001, 344 : 47 2-8 0 http://amedeo.com/lit.php?id=11172188 15 Delaugerre C, Valantin MA, Mouroux M, et al Re-occurrence of HIV- 1 drug mutations after treatment re-initiation following interruption in patients with multiple treatment failure AIDS 2001, 15: 218 9-9 1 http://amedeo.com/lit.php?id=116 849 40 16 Devereux HL, Youle... Nat Med 1998, 4: 20 8-1 4 http://amedeo.com/lit.php?id= 946 1195 37 Parekh B, Phillips S, Granade TC, et al Impact of HIV type 1 subtype variation on viral RNA quantitation AIDS Res Hum Retroviruses 1999, 15:13 3 -4 2 http://amedeo.com/lit.php?id=10029 245 38 Perelson AS, Essunger P, Cao Y, et al Decay characteristics of HIV- 1-infected compartments during combination therapy Nature 1997, 387:18 8-9 1 http://amedeo.com/lit.php?id=9 144 290 . Predictors of trend in CD4-positive T-cell count and mortality among HIV- 1-infected individuals with virological failure to all three antiretroviral-drug classes. Lancet 20 04, 3 64: 5 1-6 2. http://amedeo.com/lit.php?id=152 348 56 43 interruption ( 7- on-7-off) for a period of at least 44 weeks. The result: neither the viral load nor the proviral DNA increased. CD4+ T-cells and HIV- specific immune responses re- mained unchanged,. http://amedeo.com/lit.php?id=12 944 569 43 . Lisziewicz J, Rosenberg E; Lieberman J, et al. Control of HIV despite the discontinuation of antiretrovi- ral therapy. NEJM 1999, 340 :168 3 -4 . 44 . Lori F, Lewis MG,