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Viral load and CD4 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-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 reduction maximum in the first few months (Fagard 2005, Wit 2005, Skiest 2006). CD4-cell losses vary greatly between patients but may reach 200 or 300/µl within a few weeks. The higher and faster the CD4 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 immunological deterioration. The loss of CD4 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 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 has to be anticipated whenever there is viral replication in the presence of suboptimal drug levels, and thereby resistant mutants gain a selective advantage over the wild-type virus. As a result, there are concerns that resistances could develop both during the washout phase of medication (increasing viral replication with insufficient plasma levels) and on re-initiation of treatment (continued 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 interrupted 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 lymphadenopathy, 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 previous 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. Table 10.1: Example of the development of resistance due to repeated treatment interruptions* Date HAART/comments CD4 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 increased (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 cells/µl) were randomized before a salvage regimen either to a four-month treatment interruption 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-cell count at the time of interruption. The risk increased by 1.4 with every drop of 50 CD4 cells, demonstrating that severely immunocompromised patients are particularly at risk of developing AIDS during long treatment interruptions of several months. Treatment interruptions should be avoided in such patients. Newer data from the SMART Study, however, show that even with higher CD4 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 interruption 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 confirmed by studies - in fact it is striking how few studies have been based on this theme. 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 metabolic complications during STIs was actually increased (El Sadr 2006, see below). 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 improves, 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 treatment interruption, is theoretically useful to limit long-term toxicity on HAART, to date, a convincing argument has not been provided by the data. 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 approximately 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 remained 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? No one knows the answer, even today. There may be a completely different explanation: it is possible that certain host factors in this patients which have not yet been investigated influenced the course of disease - completely independently of HAART, STI or hydroxyurea. Nevertheless, STI has been extensively investigated in acutely infected patients (see "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 immune responses (Haslett 2000, Garcia 2001, Lori 2000, Ortiz 1999, Papasavvas 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 for ten-week treatment cycles, each consisting of eight weeks HAART and two weeks of treatment interruption. After this, HAART was permanently interrupted. Treatment success - defined as a viral load below 5,000 copies/ml without HAART after 52 weeks - occurred 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 infection, improvement of HIV-specific immune response seems unlikely in the setting of chronic HIV infection. SSITT clearly showed that treatment interruptions on immunological 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 seem questionable, are still in the experimental phases and are 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 quickly. 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). PI mutations are the first to disappear, while NNRTI mutations are more protracted because they minimally 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 described (Walter 2002), who was not able to attain sufficient viral suppression despite 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 suppressed 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 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 previously (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 effective 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 comparison 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 benefits, treatment interruptions are not justified as salvage strategies outside clinical studies, at least in severely immunosuppressed patients. Structured intermittent treatment, fixed intervals In the initial phase following interruption of HAART, the viral load usually continues 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 infected patients with more than 300 CD4 cells/µl and a viral load below 50 copies/ml were switched to a combination of d4T+3TC+indinavir/r. This combination 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 cells and HIV-specific immune responses remained 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 reported 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 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, although 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 increase) 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 treatment seem to be unfavorable. Results from a randomized NIH study with fixed intervals (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 resistance mutations. (Marchou 2006), the studies that indicate fixed interruptions as being susceptible to the development of resistance mutations 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-cell count. In other words, in patients with a good CD4 cell count, HAART is interrupted until the CD4 cell 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 heterogeneous 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 administration 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 interruptions are safe, two other studies, Trivacan and SMART came to other conclusions. Table 10.2: Randomized studies in which therapy was continued or interrupted based on CD4 cell count Source n CD4 cells at entry CD4 cells at restart Results based on clinical findings in STIs Ruiz 2005 TIBET 201 > 500 > 6 Mo < 350 or VL > 100,000 6 % ARS, otherwise STIs clinically safe. Average STI-duration 44 weeks. de novo NNRTI resistances. El Sadr 2006 SMART 5472 350 < 250 Morbidity and mortality risk low, but significantly raised! See Table 10.3. Danel 2006 Trivacan 326 > 350 < 250 Morbidity significantly raised (double), due to invasive bacterial infections. Ananworanich 2006 Staccato 430 > 350 < 350 After 484 PY: clinically safe (slightly more side effects in HAART arm; more candidiasis in STI arm). No evidence of resistances. Skiest 2006 ACTG 5170 167 > 350 < 250 In general, safe, with risks only elevated when CD4 nadir was low. ARS = acute retroviral syndrome; FU = follow up; Mo = months; PY = patient years In particular, the results of the SMART Study, which started in 2002, caused a sensation. In this, the largest randomized HIV study of all time, the cut off levels for stopping HAART were at least 350 cells/µl, and 250 cells/µl for re-instating it. This study was very successful worldwide. In the end, 318 centers in 53 countries had recruited a total of 5,472 patients (90 % of the planned 6,000 patients) were included. In January 2006, following an intermediate evaluation, an independent data safety monitoring board concluded that therapeutic interruptions result in an increased risk of AIDS - in the interruption arm, approximately twice as many AIDS illnesses were observed at follow-up, over an average of 15 months. This included severe opportunistic infections as well as malignant tumors. In fact, the overall risk was low, but so significantly elevated that the unusual and far-reaching decision was made to abort the study. In addition, it was surprisingly observed that cardiovascular incidents in the interruption arm did not (as was hoped) become less frequent, but actually increased. The clinical incidents in SMART (details on the SMART website: http:/www.smart-trial.org/news.htm) are shown in the following table. Table 10.3. Incidents occurring in SMART, for every 100 patient years (El Sadr 2006) STI (n) Control (n) Hazard ratio Progression of disease or death 3.7 (120) 1.3 (47) 2.6 (1.9-3.7)* Death 1.5 (55) 0.8 (30) 1.8 (1.2-2.9)* Cardiovasc./renal/hepatic events 1.8 (65) 1.1 (39) 1.7 (1.1-2.5)* Grade IV toxicity 5.0 (173) 4.2 (148) 1.2 (1.0-1.5)* *Significant difference. At present, the cause of these surprising results can only be speculated. What was conspicuous, however, was that the risk of disease was increased mainly in those patients whose viral load was below the borderline level at the time of interruption. In contrast, an increased risk of AIDS or death was not associated with CD4-cell count at the start of the study. Even the CD4 nadir or a previous diagnosis of AIDS (approximately 24 % of the patients) surpisingly was not predictive. Severe events such as AIDS or death also occurred with good CD4-cell counts. For many experts, SMART laid to rest the concept of interrupting therapy as a method of treatment. However, some points of criticism remain. Much of SMART has not yet been evaluated, and the type of clinical events and patients have to be evualated more closely. Despite the increased risk of progression, it is important not to lose sight of the proportions. Overall, the risk of becoming ill was low, and in SMART an essential point for stopping and restarting HAART was not noted: the CD4-cell percentage. Only the absolute CD4-cell counts were used as criteria, although the percentage values have been required to be included in therapeutic decisions for many years (Goicoechea 2005, Hulgan 2005). In our opinion, it is still too early to completely dismiss the concept of CD4-driven treatment interruptions. In the first instance SMART has shown that treatment interruptions such as these, and in this design are not beneficial. Practical tips for treatment interruptions § Don't try to convince patients to interrupt therapy - if there are no problems with HAART, there is no reason to stop it. § To reverse resistance or for immunological reasons - i.e., as a "strategy"- STIs are not useful. § A positive effect on cardiovascular incidents or lipodystrophy has not been confirmed. Following the SMART Study, this is highly unlikely. § Nevertheless, the patient's wish for a break should be respected! The interruption will be made anyway, whether the clinician agrees with it or not. § A supervised treatment interruption is still always better than one undertaken without the awareness of the clinician. § Beforehand, information should be provided on clinical (retroviral syndrome, AIDS), immunological (loss of CD4 cells) and virological (resistance) consequences. § Patients must be aware that the risk of infection increases - even after a longer suppression, viral load returns to initial levels after 4-6 weeks without HAART. § Beware HBV co-infection (danger of hepatitis flaring up again)! § CD4 cells (including percentage), viral load, and blood count (thrombocytes!) should be monitored monthly during interruptions. § Risk of resistance is possibly higher with NNRTIs (choose robust regimens and stop NNRTIs several days earlier if possible - consider the half-life of the drugs). § Patients who started HAART "too early" according to current standards can probably interrupt quite safely. § Resistance testing during treatment interruptions is not useful - it usually only identifies wild-type virus. § Start with HAART again, in good time after the treatment interruption! 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