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Antiretroviral Therapy
(Part XXIV)

Update from the International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication

November 7, 1997

AIDS Information Center VA Medical Center, San Francisco

Protease Inhibitor Resistance and Drug Failure

Virological outcomes in ACTG 320, a randomized, placebo controlled trial of indinavir in combination with two nucleosides

ACTG 320 is a recently completed randomized, double blind, placebo controlled study of zidovudine (AZT) and lamivudine (3TC) vs. the combination of AZT, 3TC and indinavir (Crixivan). The study enrolled 1156 subjects, all with a CD4+ T cell count less than 200 cells/cc. Subjects were 3TC and protease inhibitor naÐve at study entry. After a median follow-up of 38 weeks, a significant clinical benefit was observed in the indinavir arm (hazard ratio 0.50, CI 0.33 to 0.76).

In a virology substudy, 374 subjects were analyzed in using the Amplicor HIV-1 RNA assay (lower limit of detection 500 copies/ml). The baseline HIV-1 RNA was approximately 5.0 log (100,000) copies/ml in both treatment groups.

After 24 weeks of therapy, 3% of patients on AZT and 3TC had undetectable levels of HIV-1 RNA, compared to 60% in the AZT, 3TC and indinavir arm. In the cohort who initiated three drug therapy with a baseline CD4+ T cell count less than 50 cells/cc, only 40% maintained undetectable levels of HIV-1 RNA through week 24. These trends persist through week 40. Finally, a high viral load or low CD4+ T cell count at baseline was highly predictive of drug failure [Hammer, abstract 67].

Comment: The ACTG 320 experience suggests that about one half of patients who initiate AZT, 3TC and indinavir late in the natural history of the disease process can expect to obtained long-term, complete viral suppression. This is a much lower number than previously reported (Merck 035). HIV therapy should therefore be initiated early.

Nelfinavir resistance: significance of pre-existing natural polymorphisms

Amy Patick from Agouron reviewed her data from 170 patients treated with nelfinavir (Viracept). As reported before, nelfinavir failure is strongly associated with the D30N substitution. D30N rarely evolves alone, and is often seen with mutations at positions 10, 35, 36, 62, 63, 71, 77, 88 (among others). Many of these mutations exist as natural polymorphisms (i.e., they are present at low frequencies in untreated patients). The significance of these polymorphisms remains unclear. In this study, the presence of these polymorphisms at baseline did not predict subsequent failure to nelfinavir.

Notably, 5% of patients failing nelfinavir developed L90M (which is associated with high-level saquinavir resistance) [Patick et al, abstract 18].

Comment: The HIV-1 protease gene is highly variable, even in the absence of protease inhibitors. Many "mutations" seen with therapy are actually natural polymorphisms. This study suggests that the presence of these polymorphisms does not predict failure to a drug.

Resistance after long-term saquinavir therapy

Researchers at Stanford University performed genotypic and phenotypic assays on viral isolates from 40 patients who "failed" long-term therapy with saquinavir (Invirase). As expected, most patients (58%) developed G48V or L90M. The G48V occurred more frequently in patients treated with high dose saquinavir. A significant percentage of patients (38%) also had mutations typically associated with other protease inhibitors, including M36I, M46I, V82A, and I84A.

All patients (6 of 6) who developed G48V eventually developed V82A (a mutation associated with resistance to indinavir or ritonavir), either while on continued saquinavir or after switching to nelfinavir or indinavir. V82A did not typically develop in the presence of L90M [see also Eastman, abstract 30; Deeks, abstract 69].

Comment: The development of complex mutation patterns was common in patients after prolonged (> 1 year) treatment with saquinavir. In such patients, cross-resistance to other protease inhibitors would be expected. Preliminary data from this presentation, and others, suggests that the resistance pathway taken by the virus may be influenced by the initial presence of L90M vs. G48V.

Indinavir resistance following saquinavir therapy

Sequential protease inhibitor therapy was a common theme at this year's conference. In this study, 54 patients were treated with saquinavir (Invirase) and followed prospectively. Twenty-two of these patients eventually failed saquinavir and were switched to indinavir (Crixivan). Ten of the 22 patients had a durable response to indinavir, while 12 eventually failed. Failure was defined as having a viral load greater than 3.5 log copies/mL after a mean 4 month period of treatment with indinavir.

Genotypic analysis was performed on the 12 patients who failed indinavir. Prior to the introduction of indinavir, 5 of the 12 patients had a mutation at position L90M. All 5 patients maintained L90M in the presence of indinavir; none developed the classic indinavir associated mutation V82A. A previously uncharacterized mutation, G73S, was observed in all post-indinavir specimens.

In the other 6 patients who failed indinavir after prolonged saquinavir thearapy, saquinavir related resistance patterns were not present at the time of the switch. Surprisingly, after switching to indinavir, all patients failed with typical saquinavir related mutations (L90M or G48V). Typical indinavir related mutations, such as V82A, were rare [Dulioust et al, abstract 16].

Comment: These results suggest that saquinavir related genotypic resistance confers cross-resistance to indinavir in vivo, despite the lack of significant cross-resistance in vitro. Furthermore, patients may have a normal viral genotype (i.e., no mutations evident on genotypic analysis) after prolonged therapy with saquinavir, yet still rapidly select for saquinavir related mutations in the presence of indinavir. This suggests that these mutants pre-existed below the levels detectable with current genotypic assays.

Acquisition of genotypic resistance associated with reduced susceptibility to saquinavir (hard gel capsules)
Acquisition of genotypic resistance associated with saquinavir (soft gel capsule)

Eastman and colleagues performed genotypic assays on 7 patients who initially responded to and eventually failed saquinavir (hard gel capsule). Viral rebound was associated with the development of an L90M mutation alone (n=4), G48V alone (n=2) or both (n=1). All 3 subjects with the G48V mutation developed subsequent additional mutations, including the V82A mutation typically seen with indinavir or ritonavir resistance. Two subjects acquired an L90M mutation that was subsequently lost in the presence of the V82A mutation [Eastman et al, abstract 30].

In a companion presentation, 13 patients added an experimental formulation of saquinavir (saquinavir-soft gel capsule) to a stable nucleoside analogue regimen. After 8 weeks of therapy, a potent 1.7 log decrease in plasma HIV-1 RNA was observed. Six patients subsequently failed (defined as a viral rebound of > 1 log). Viral rebound was associated with L90M (n=1), G48V (n=1) or both (n=2). One patient rebounded with V77E only (results from the sixth patient were not available). Interestingly, one patient with prior ritonavir failure switched to saquinavir soft-gel capsule. At the time of the switch, this patient had three mutations associated with high-level resistance to indinavir and ritonavir (mixed V82V/A, M46M/L and I84I/V). As expected, SQV-SGC selected for L90M, but V82, M46 and I84 all reverted to wild-type. This patient subsequently switched to indinavir, and has had a durable 7 month response, despite the prior presence of mutations highly correlated with indinavir resistance [Deeks et al, abstract 69].

Comment: These two studies confirm that G48V and L90M are the two most important mutations associated with saquinavir therapy. They also suggest that L90M may not be compatible with V82A, particularly when other so-called "compensatory mutations" are not present [see also Winters, abstract 17].

Nelfinavir and indinavir therapy following failure of saquinavir

In a companion study to Winters et al (abstract 17), Jody Lawrence from Stanford reported on 16 patients who switched to nelfinavir (Viracept) after failing saquinavir. When possible, nucleoside analogues were modified. Patients switched to nelfinavir after a mean duration on saquinavir of 11 months.

After 4 weeks of therapy with nelfinavir, the mean decrease in HIV-1 RNA was 0.56 log. Only 2 of 16 subjects had a > 0.5 log decline through week 12 of nelfinavir therapy. At week 12, 2 patients failing nelfinavir had evidence of D30N, the classic mutation associated with nelfinavir resistance. Most patients who failed nelfinavir had mutations typically seen with other protease inhibitors.

Considering the poor response to nelfinavir, the study was modified. Ten patients who failed nelfinavir were switched to indinavir (Crixivan) plus nevirapine (Viramune). After 4 weeks of therapy, the mean reduction in viral load was 1.8 log. The durability of this potent response is unknown [Lawrence et al, abstract 64].

Comment: In this study, saquinavir resistance conferred cross- resistance to nelfinavir. Therefore, the utility of nelfinavir in patients with prolonged prior saquinavir may be limited. On the other hand, the combination of indinavir plus nevirapine appeared to be very active over 4 weeks of follow-up, despite the fact that these patients had failed two protease inhibitors. The long-term efficacy of indinavir plus nevirapine as salvage therapy is unknown. Finally, resistance patterns to a particular protease inhibitor can be very different when the drug is used in patients who have already failed a first-line protease inhibitor.

Viral resistance to the combination of ritonavir and saquinavir

The combination of ritonavir and saquinavir is extremely effective in suppressing HIV-1 replication. In an ongoing study of this combination, approximately 80 to 90% of subjects have had a durable virologic response. In this study, genotypic analysis was performed on viral isolates from fivepatients who exhibited a rebound in viral load. Rebound was associated with the emergenceof V82A and I54V in all five patients. I84V and M36I were also seen. L90M and G48V, both typically seen with saquinavir failure, were not observed [Molla et al, abstract 83].

Comment: Patients who fail the combination of ritonavir and saquinavir appear to select primarily for ritonavir related mutations. Since ritonavir resistance is known to confer cross resistance to saquinavir, this observation is perhaps not surprising. More resistance data on this combination is needed.

Drug resistance genotypes from plasma virus of HIV-infected patients failing combination drug therapy
Genotypic analysis of HIV-1 protease from patients failing highly active anti-retroviral therapy

Several groups reported cross-sectional results from patients failing combination therapies.

One group, studying viral isolates from the military health care system, reported that 21% of patients failing a combination regimen had no evidence of genotypic resistance. Surprisingly, over 50% of patients failing a protease inhibitor-containing regimen had no genotypic changes in the protease gene [Mayers et al, abstract 80].

In a study of patients in the Denver area, 33 patients failing a protease inhibitor containing regimen were analyzed (most patients had received indinavir). Compared to the clade B consensus sequence, patients failing combination therapy had a mean of 4 mutations in their protease gene. Four of the 33 subjects had no protease mutations. Despite the infrequent use of saquinavir, L90M was very common (15 of 37 isolates) [Young et al, abstract 65].

Comment: The clinical experience with protease inhibitors in the primary care setting is likely to be very different from the experience seen in controlled clinical trials. These studies illustrate this point. The observation that many patients fail without genotypic evidence of resistance may be due to several factors: (1) variable drug absorption, (2) enhanced drug metabolism, (3) poor adherence to the drug regimen and/or (4) limited sensitivity of the genotypic assays.

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