More? HIV Medicine 2007, Chapter 5.7: Download

HIV Medicine
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7.1 Change due to acute side effects Not every acute side effect requires immediate modification or complete cessation of therapy. Mild nausea or diarrhea can occur in the beginning and should be tolerated. Gastrointestinal side effects that occur during the first weeks are not dangerous, are treated easily (see "Side Effects"), and often improve spontaneously. The same is true for mild CNS disorders on efavirenz or mild allergies. However, certain adverse drug events (see box) almost always require immediate alteration of HAART, as they could seriously endanger the patient. Side effects that almost always require alteration of HAART · Severe diarrhea, which persists despite loperamide even after several weeks (usually due to nelfinavir, lopinavir, fosamprenavir) · Severe nausea, which persists despite metoclopramide, which requires continuous treatment or leads to significant weight loss (usually AZT, ddI) · Polyneuropathy (d4T, ddI, possibly also 3TC - often resolves very slowly, therefore change treatment quickly!) · Severe anemia (AZT) · Severe, progressive muscular weakness (d4T!, ddI!) · Pancreatitis (ddI, ddI+TDF!, d4T+ddI+HU! In rare cases lopinavir/r) · Lactic acidosis (most often d4T+ddI, but also all other NRTIs) · Severe allergies with involvement of mucous membranes, fever (typically abacavir, NNRTIs, more rarely fosamprenavir) · Renal failure (tenofovir, indinavir) · Nephrolithiasis (indinavir) · Hepatotoxicity with transaminases > 5 x normal values (nevirapine, tipranavir) · Jaundice (nevirapine, atazanavir, indinavir, tipranavir) · Severe repetitive onychitis (indinavir, possibly also 3TC) · Psychosis (efavirenz, possibly also AZT) 7.2 Change due to long-term toxicity In the last few years, many clinicians have changed virologically successful combinations to minimize cumulative long-term toxicities (especially lipodystrophy and dyslipidemia). In particular, PIs and d4T are replaced with NNRTIs or other NRTIs. The most important studies are discussed below. PI replacement Replacement of PIs by NNRTIs or NRTIs is virologically safe, if the viral load is well suppressed (Table 7.1). It seems to work reasonably effectively on the lipid levels, but the effect on lipodystrophy is much weaker. Lipid levels are most likely to improve after switching to abacavir, and are least likely to do so on efavirenz. Quality of life improved significantly in the switch arms of most studies, probably due to the reduced pill burden. Previous NRTI experience increases the risk of virological failure following the switch to abacavir. Finally, there is also the potential side effects of the new medications, which have been introduced, have to be heeded: a rash or hepatotoxicity can be expected with nevirapine, CNS disturbances with efavirenz. The hypersensitivity reaction with abacavir is a threat, which had a frequency of 10 % in the TRIZAL study (Katlama 2003). A meta-analysis also showed that the change to a PI free regimen is associated with a lower rise in CD4 cells (Owen 2004). It is possible that the PI does not always have to be replaced by another class. With dyslipidemia, a change to atazanavir can be considered (Wood 2004, Gatell 2006), although in our experience it has little effect on lipodystrophy. Table 7.1: Randomized studies on switching from PIs to other drugs Source N Wk Viral load Effect Effect of switch on lipids (L) or lipodystrophy (LD) PI ? NVP Barreiro 2000 138 24 Advantage L unchanged, LD better Ruiz 2001 106 48 n.s. L better, LD unchanged Arranz-Caso 2005 160 48 n.s. L better, LD better PI ? EFV Becker 2001 346 48 Advantage L unchanged Molina 2005 355 48 Advantage L/LD n.a., side effects similar PI ? ABC Clumeck 2001 211 24 Advantage L better, LD subjectively better Opravil 2002 163 84 Disadv. (trend) L better, LD unchanged Katlama 2003 209* 48 n.s. L better, LD better Keiser 2005 104 28 n.s. L better PI ? EFV v NVP Negredo 2002 77 48 n.s. L only better on NVP, LD unchanged Calza 2005 130 48 n.s. L actually worse, if the PI-arm contained lipid reducer PI ? EFV v NVP v ABC Martinez 2003 460 48 Trend against ABC L only better on ABC. LD probably unchanged All studies (except Martinez 2003), were openly randomized against the continuation of PIs. All patients had been on PIs for several months at the time of the switch, with undetectable viral load. Viral load in the switch arm versus the continuing arm. Wk = weeks, LD = lipodystrophy, L = lipids, n.a. = not available, n.s. = not significant. *Only 62 % were taking a PI, the rest were on NNRTIs or triple nuke. d4T replacement The thymidine analog d4T, which plays a leading role in mitochondrial toxicity (see corresponding section), is also frequently replaced with other NRTIs. The switch studies were mainly smaller, however, and sometimes the PIs were replaced at the same time (see Table 7.2). Table 7.2: Randomized studies on switching from d4T to other drugs Source N Switch Wk Effect of switch Carr 2002 Martin 2004 106 ABC instead of d4T or AZT 104 LA better, lipids unchanged John 2003 37 AZT instead of d4T and ABC instead of PI 48 LA of limbs slightly better, lipids and abdominal fat unchanged Moyle 2003 30 ABC instead of d4T or PI/NNRTI, or AZT+ABC instead of d4T+PI 48 LA better (when replacing d4T) Lipids better (when replacing PI) McComsey 2004* 118 AZT or ABC instead of d4T 48 LA better, lactate better Milinkovic 2005 56 TDF or d4T-reduction to 30 mg instead of d4T 24 LA, lipids better (TDF effects stronger than d4T reduction) Moyle 2006 105 TDF or ABC instead of d4T or AZT 48 LA better, lipids better on TDF Murphy 2006 101 ABC or nuke sparing instead of d4T or AZT 48 LA better No study showed any difference with respect to virological failure. Wk = weeks, LA = lipoatrophy. McComsey 2004/Moyle 2005: only patients with LA were investigated. * The study was not randomized. Despite the heterogeneity of these studies, they clearly demonstrated that lipoatrophy improves if d4T is replaced. In particular, the subcutaneous fat of the limbs increases, although at first the improvement is often unrecognizable clinically and can only be detected in DEXA scans (Martin 2004). Histological investigations have shown that the elevated rate of apoptosis in adipocytes normalizes when d4T has been replaced (Cherry 2005, McComsey 2005). It therefore seems to be advisable to replace d4T with another NRTI. With abacavir, however, the HSR remains a problem, occurring in 10 % of patients in the Mitox Study (Carr 2002). It should also be noted that it is never certain whether the viral suppression will persist under a new regimen. Particular caution has to be taken when there has been long-term pretreatment. One example of what could happen with a strategic change is shown in Table 7.3. This case also shows how carefully one has to approach changes if there has been inadequate dual-therapy in the past. The ice is thin! Table 7.3: Example of what could happen on switching drugs. (n.k. = not known) Date (HA)ART CD4 cells Viral load 1996-98 AZT+ddC n.k. n.k. Since 1998 AZT+3TC+NFV (always under the detection limit) n.k. n.k. Nov. 2002 Findings: significant lipoatrophy. Decision to switch 688 < 50 Feb. 2003 ABC+3TC+NFV* 788 < 50 Apr. 2003 ABC+TDF+NVP (= planned ART, see notes) 871 < 50 May 2003 Severe rash, ALT/AST > 500 U/l n.k. < 50 Jun. 2003 ABC+TDF+3TC Aug. 2003 Resistance: M41L+D67N+M184V+L210W+T215Y 679 37,400 Sep. 2003 AZT+3TC+NFV n.k. 59,100 Oct. 2004 743 < 50 *On account of lipodystrophy, the combination of ABC+TDF+NVP was planned in February 2003, but due to potential allergic reactions to ABC and NVP, it was changed in two steps. Rash with hepatic involvement did indeed occur on NVP in April 2003, so that NVP was replaced by 3TC - triple nuke! The resistances that were then detected were almost certainly present under AZT+ddC, but sufficiently suppressed by PI therapy. Surprising is the good reaction after the reintroduction of the former therapy. Switching to tenofovir In studies on therapy-naïve patients, tenofovir had considerably lower mitochondrial toxicity than d4T or AZT. In the 903 Study tenofovir was tolerated significantly better than d4T (Gallant 2004, 2006). Switching to tenofovir can also help to reduce side effects (Domingo 2004). In the 903 Study, lipids improved when d4T was switched to tenofovir (Suleiman 2004). In a retrospective study, both lipids and liver enzymes improved (Schewe 2006). The mitochondrial DNA that was depleted by d4T seems to improve (Ribera 2003). However, only a few randomized studies have been performed on switching thymidine analogs to tenofovir. In 105 patients with lipoatrophy, who had the thymidine analog replaced by either tenofovir or abacavir, the clinical changes after 48 weeks were the same, but lipids improved more significantly on tenofovir (Moyle 2006). In view of the poor efficacy of TDF-containing triple nuke combinations (see corresponding section), one should avoid these wherever possible (Hoogewerf 2003, Perez-Elias 2005). One example is shown in Table 7.3. In practice, changes are often made, which go further than PI and/or d4T/AZT simply due to concerns over long-term toxicity. This (e.g. abacavir or tenofovir instead of ddI) is based on laboratory studies showing a hierarchy with respect to mitochondrial toxicity (see also section on mitochondrial toxicity). In addition, there are reports on simplification of therapy, in which mono- or nuke-sparing strategies are used (see below). There is so far no evidence of a clinical benefit. Therefore, it is currently advisable to wait for the results of the corresponding clinical studies. Switch to nuke sparing Some studies have also tried to avoid NRTIs altogether. These "nuke sparing" strategies have even been tested on therapy-naïve patients, too (see previous chapter) and following the results of the ACTG 5142 study, could play a role in the future (Riddler 2006). In ACTG 5142, nuke sparing was virologically effective and beneficial with respect to lipoatrophy; however, the tolerability was no better than in conventional regimens. In fact, dyslipidemia was observed more frequently (Riddler 2006). In the largest study to date, ACTG 5116 (Fischl 2007) in 236 patients on an effective HAART, the change to lopinavir/r plus efavirenz in comparison to efavirenz plus 2 NRTIs led to an increased rate of discontinuation, due as much to virological failure as to side effects. The results of this study are in contrast to several other studies (see Table 7.4) and to the results of lopinavir/r plus efavirenz in therapy-naïve patients (Riddler 2006). At present, it seems to be too early to recommend nuke sparing as a switch strategy. Of course, this also applies to the monotherapy with boosted PIs (see next chapter). Table 7.4: Studies of switching to nuke sparing with PI plus NNRTI Source n Switch Wk Effect of the switch Lopez-Corles 2003 42* SQV/r + EFV 48 Virologically good Tebas 2005 (ACTG 5125) 62 LPV/r + EFV 48 Diverse metabolic disturbances, lipoatrophy better Negredo 2005 (NEKA) 16* LPV/r + NVP 48 Virologically good, lipids and mitochondrial DNA better Boyd 2005 (HIVNAT 009) 26* IDV/r + EFV 48 Virologically good, but many SE from IDV, LA possibly somewhat better Fischl 2007 (ACTG 5116) 118* LPV/r + EFV 110 Trend to more virological failure, more SE Murphy 2006 (ACTG 5110) 101 LPV/r + NVP 48 Virologically safe, lipodystrophy better LA = Lipoatrophy, SE = side effects * im Switch-Arm 7.3. Switch for virological treatment failure The change in treatment due to virological failure requires a certain degree of finesse, but also decisiveness! There is a great potential for mistakes to be made. It is important to explain to the, often skeptical, patient ("Shouldn't I save other drugs for later?") when and why changes have to be made. HAART should be rapidly changed in the case of insufficient viral suppression and/or after an increase in plasma viremia, otherwise there is a risk of new resistance mutations, which may eliminate future treatment options. First-line therapy with AZT+3TC+indinavir is a good example. If this regimen fails but the patient continues this regimen, the virus accumulates further mutations (including TAMs) such as 41L, 67N, 210W, 215F, 184V, 82T, 84V, 46L, 90M - and this eliminates all other currently available drugs with the exception of NNRTIs and ddI (and T-20). If an NNRTI is added, most options disappear. Even individual mutations can be a problem: K65R, which very frequently occurs on failing tenofovir-containing triple nuke therapies, leads to considerable loss of efficacy for ABC, 3TC, FTC and probably ddI. Viral replication in the presence of insufficient plasma levels is ideal for the development of resistance mutations. In the case of clear virological failure, action must be taken without delay - the longer one waits, the more difficult things become. Insufficient viral suppression means a viral load above the level of detection of 50 copies/ml. Some clinicians, however, tolerate values up to 500 or even 1,000 copies/ml. In patients with good options for subsequent regimens and good compliance, we consider this delay unwise, with a few exceptions. Currently, several trials are underway to investigate two randomized strategies in patients, in whom several HAART combinations have failed: either change immediately, or when the viral load reaches a certain level ("early versus deferred switch"). The preliminary results indicate that even in such cases, one can wait a short time (Nasta 2006, Riddler 2006). Arguments for rapid management of virological treatment failure Argument for waiting with virological treatment failure The virus will take the opportunity to generate further resistances New therapies always carry the risk of new toxicities/intolerabilities, which can necessitate interruption of treatment Options are preserved With low viremia, most patients are immunologically stable for a long time (at least clinically) The less resistances that are present, the more successful the switch The replicative fitness is often reduced, and this often remains under therapy The lower the viral load by the switch, the better the effect of the new therapy With a lower viral load, resistance testing is often not possible; although resistance mutations are already present, one makes the switch "blind" The new regimen is often no more complex than the actual one - sometimes, it is possible to simplify it (once daily, d4T/ddI out, etc.) It is often difficult to convince patients to change a well-tolerated simple regimen In cases of clinical treatment failure (AIDS) or immunological failure (stagnation or decrease in the level of CD4 cells), in which the viral load is below 50 copies/ml, the value of a change in therapy is uncertain. Some combinations such as TDF+ddI, however, are rather unfavorable for immunological reconstitution; such combinations should be changed. Otherwise, by switching HAART alone, one hardly improves anything. It is important that when virological failure occurs, the individual situation of the patient is carefully analyzed. In particular, several questions need to be addressed: What are the reasons for the measurable viral load? A viral load above 50 copies/ml does not necessarily mean that resistance mutations have developed. The plasma drug levels may be insufficient (measure the plasma levels!) - which, in turn may be due to: drug malabsorption, drug interactions or insufficient dosing (e.g. in very big, heavy patients). Compliance is also critical. Any possible difficulties associated with the taking of the drugs should be openly addressed: Is it the number of pills? Do restrictions in food intake cause problems? Would once-daily treatment be better? Are there other reasons, such as depression? The risks of resistance developing as a result of non-compliance should be reiterated. If plasma levels are sufficient and viral load remains detectable (monitor blips occurring within a few weeks!), treatment should be changed as soon as possible. How vulnerable is the present combination? NNRTI regimens are very sensitive, as cross-resistance can develop particularly rapidly for the whole class. Thus, a prompt change in therapy is even more vital than with the other drug classes. Delaying this by even a few days or weeks may be too long! Rapid development of resistance can also be expected with 3TC (and FTC). A PI-containing regimen without an NNRTI may allow a little more time, but the credo still applies: the higher the viral load at the time of modification, the lower the chances of success. One should not wait too long. What options does the patient have, and what are the consequences of the change in therapy? The more options that remain available, the sooner they should be utilized. Therapy can often be intensified quite easily (e.g. adding abacavir plus an NNRTI). In such cases, the decision to change or intensify a regimen is less difficult. On the other hand, it may be advisable to continue therapy in a patient with three NRTIs, even if the plasma viremia is not completely suppressed. Often, the viral load does not rise above the baseline value, and the CD4 cells remain stable or even increase. Some experts advocate waiting in these cases. Resistances to nucleoside analogs are to be expected, and therefore NNRTIs and PIs can be saved from the start. Even when multiple resistances are already present, one is probably able to wait initially (see above). In all cases, it has to be clarified beforehand whether the patient is eligible for an intensification of therapy. A patient on triple-class therapy as well as extensive pre-treatment usually has few options left. These are often reduced even further by side effects. In such cases, the goal of achieving a viral load below the level of detection may have to be abandoned (see also "Salvage Therapy"). References See at the end of the next chapter.