Protease Inhibitors
The antiviral effects of saquinavir soft gel capsules and of indinavir, when given with ZDV and 3TC to protease inhibitor- and 3TC-naïve patients who had received ZDV for less than 12 months in the CHEESE study, were comparable. (Abstract 387b.)
Coadministration of saquinavir soft gel capsule with nelfinavir, indinavir, or ritonavir resulted in increases in the saquinavir AUC by 392%, 620%, and 20-fold, respectively. (Abstract 354.)
In several patients receiving saquinavir monotherapy, the L90M mutation was lost in the presence of a G48V/V82A double mutation. (Abstract 397.)
One hundred fifty protease inhibitor-naïve patients were randomized to receive, in addition to two nucleoside analog reverse transcriptase inhibitors, saquinavir soft gel 1200 mg tid, nelfinavir 750 mg tid, or saquinavir soft gel 800 mg tid plus nelfinavir 750 mg tid, while a fourth arm was randomized to receive saquinavir soft gel 800 mg tid plus nelfinavir 750 mg tid without other drugs. The best results were produced by the four-drug combination at 24 weeks, with 75% of subjects (and 100% of those who had been completely antiretroviral-naïve) having plasma HIV RNA less than 50 copies/mL. (Abstract 394b. )
Nine of 10 subjects on a multi-drug regimen including saquinavir soft gel 800 mg tid and nelfinavir 750 mg tid had less than 500 copies HIV RNA per mL of plasma at 11 months. (Abstract 394c.)
Coadministration of saquinavir soft gel capsule with clarithromycin resulted in a 45% increase in AUC of this macrolide antibiotic and a 177% increase in saquinavir AUC. (Abstract 354.) Thus, the new formulation of saquinavir is clearly superior to the older formulation.
Ritonavir, Indinavir, Nelfinavir
Fifty-five patients with CD4+ lymphocyte counts between 100 and 300 cells/mm3 were treated with ZDV, 3TC, and ritonavir. At 48 weeks, there was a significant rise in naïve (RA+CD62L+) CD4+ T cells beginning with the first month of therapy, decreased evidence of T cell activation, and enhanced skin test responses to tetanus, Candida, trichophyton, or PPD. There was, however, no increase in lymphocyte proliferative responses to HIV antigens, tetanus toxoid, candida, streptokinase, or alloantigens. (Abstract LB14.)In a single-dose evaluation, ritonavir AUC was increased by 40% in the presence of mild hepatic impairment (Child-Pugh classification), raising the consideration of possible dose reduction in such patients. Doses of 500 mg bid or less may be safe and effective. (Abstract 359.)
Twenty protease inhibitor-naïve patients received ritonavir 400 mg q12h and nelfinavir 500 mg or 750 mg q12h with a resultant median 1.72 log10 decrease in plasma HIV RNA and median 85 cells/mm3 increase in CD4 count at four weeks. (Abstract 394a.)
Substudy analysis of ACTG 320 found that, in patients receiving ZDV, 3TC, and indinavir, patients with baseline CD4 count less than 50 cells/mm3 were significantly less likely to achieve plasma HIV RNA less than 500 copies/mL than those with higher CD4 counts at study enrollment. The strongest predictor of an undetectable viral load at 24 and 40 weeks was the plasma HIV RNA concentration at week 4. (Abstract 509.)
Eighty-seven patients who were protease inhibitor- and 3TC-naïve received ZDV and 3TC and were randomized to also receive indinavir in one of three dosing regimens: 800 mg q8h, 1000 mg q12h, and 1200 mg q12h. Data on 46 patients at week 20 demonstrated comparability in results across treatment groups with 46%, 76%, and 75% having, respectively, less than 50 plasma HIV RNA copies/mL. These data suggest that these bid indinavir dosing regimens may be effective. (Abstract 374.)
3TC-naïve patients with less than six months of prior nucleoside analog therapy were given d4T and 3TC and were randomized to also receive nelfinavir in one of two dosing regimens-750 mg tid or 1250 mg bid. In a subset of 21 patients studied after four weeks, the median plasma trough concentration of nelfinavir was 0.7 mg/L in the bid group and 1.0 mg/L in the tid group. Analysis of another subset of patients after 16 weeks found that 83% of 58 patients assigned bid dosing and 78% of 23 assigned tid dosing had plasma HIV RNA less than 400 copies/mL. These data suggest that this bid nelfinavir regimen may be as effective as the standard tid regimen. (Abstract 373.)
Two studies concluded that nelfinavir is effective when given 1250 mg bid; lower doses may produce inadequate trough concentrations. Indinavir and nelfinavir given together, each in a dose of 1000 mg q12h, provide effective blood levels of these antiretrovirals. (Abstracts 373, 393.)
While bid treatment regimens are more convenient than tid regimens and may improve compliance, the studies summarized above have all been performed in small numbers of patients and are of limited duration. Thus, clinicians should remain cautious in the use of such regimens.
Amprenavir
Amprenavir (141W94) is a new protease inhibitor undergoing clinical investigation. Twenty-seven protease inhibitor-naïve patients received amprenavir 800 mg tid plus one of the following: saquinavir soft gel capsule 800 mg tid, indinavir 800 mg tid, or nelfinavir 750 mg tid. The combinations were well tolerated and were associated with a median decrease in viral load of 2.53 log10-3.18 log10 at four weeks and 1.85 log10-3.75 log10 at 16 weeks. Another group received amprenavir alone for 21 days prior to the addition of ZDV and 3TC; this group had a decrease in viral load at 16 weeks of 2.79 log10. (Abstract 6.)In ACTG 347, 92 protease inhibitor- and 3TC-naïve patients were randomized to receive either amprenavir r1200 mg qd alone or together with ZDV and 3TC. The study was aborted after a median of 88 days of therapy because of failure (virological rebound) of the monotherapy arm. Eventually, 13 virological failures occurred in this arm, compared to one in the triple therapy arm (P = 0.0009). (Abstract 512.) Failure was associated with the frequent selection of the I50V mutation; M36I, M46I, I47V, and I84L emerged less commonly. (Abstract 406a.)
Amprenavir, abacavir, ZDV, and 3TC were administered together in a bid regimen to 13 acutely infected (< 90 days) and 12 chronically infected, protease inhibitor- and 3TC-naïve patients. Plasma HIV RNA became undetectable (< 100 copies/mL) in 14 of 20 patients by eight weeks. The mean increase in CD4 count at 12 weeks was 172 cells/mm3 in the acutely infected patients and 126 in those chronically infected. Importantly, there were mean increases in naïve (CD45RA+CD62L+) CD4+ T cells of 106 and 29 at 12 weeks in the two groups, respectively, while the number of naïve CD8+ T cells increased by 76 and 61, respectively. (Abstract 363.)
Amprenavir appears to be an effective protease inhibitor. I look forward to follow-up on the 13 patients with presumed viral resistance to the protease inhibitors as a result of their participation in ACTG 347.
Hydroxyurea
The combination of hydroxyurea with ddI or with ddI plus d4T has been shown to lower viral load and, often after an initial decrease, to modestly increase CD4+ T-cell count. Hydroxyurea inhibits cellular ribonucleotide reductase, thereby decreasing the intracellular pool of deoxynucleoside triphosphates and possibly allowing increased uptake of nucleoside analogs. Since it inhibits a human, rather than a viral enzyme, the virus cannot develop resistance to it.Several relatively small studies examined the antiretroviral activity
of hydroxyurea. In one, 144 patients, 75% of whom were antiretroviral-naïve,
with a mean baseline CD4 count of 370 cells/mm3, received d4T
and ddI and were randomized to also receive either hydroxyurea or placebo.
At 12 weeks, the hydroxyurea group had lower mean viral loads, and 19%
had plasma HIV RNA less than 20 copies/mL vs. only 8% in the placebo group
(P = 0.05). Compatible with its effect on proliferating cells, hydroxyurea
administration was associated with a blunted CD4+ cell response. (Abstract
656.)
Antiretroviral Treatment Failures
Of course, reproducibility of genotype assays in various laboratories is an initial requirement for their clinical usefulness. One study suggests that such inter-laboratory reproducibility has not yet been achieved. The ENVA genotyping panel, consisting of a blinded set of nine low-concentration plasmid mixtures containing HIV-1 reverse transcriptase genes at different ratios of wild-type and mutant genotypes at amino acid positions 41, 184, and 215, was distributed to 23 laboratories in the United States and Europe. The samples were amplified and genotyped (all used automatic sequencing technologies) using the standard methodologies in place in their laboratories. In summary, the results reported were highly variable, with large differences in sensitivity and accuracy between laboratories, indicating the need for better quality assurance. (Abstract 532.)
"Rapid" phenotypic assays are also under investigation. Such assays may help to elucidate the issues of cross-resistance among the protease inhibitors. In one study, such an assay was used to examine cross-resistance by constructing 828 recombinant viruses with protease and reverse transcriptase sequences derived from plasma HIV RNA against seven concentrations of each of four protease inhibitors: indinavir, saquinavir, ritonavir, and nelfinavir. Ten-fold or greater resistance to any one of the protease inhibitors was associated with four-fold or greater resistance to all three of the other protease inhibitors in 77-95% of cases. (Abstract 395.)
Fortunately, some failing patients do respond to a change in protease inhibitors. Twelve heavily pretreated patients who had each been previously exposed to saquinavir, indinavir, and ritonavir and were failing their current therapies, were given d4T, ddI, 3TC, nevirapine, nelfinavir (1000 mg tid), and saquinavir (hard gel capsule; 600 mg tid). Viral load was reduced to less than 400 copies/mL by week 12 in all nine patients able to tolerate the regimen. CD4 count increase ranged from 30-370 cells/mm3. (Abstract 426.)
Ritonavir, saquinavir, d4T, and 3TC were administered to 19 patients (13 were 3TC-naïve) who had experienced virologic failure while receiving nelfinavir. Thirteen (68%) of the 19 had plasma HIV RNA less than 500 copies/mL after 24 weeks. (Abstract 510.)
Seventeen patients with virologic failure, despite apparent adherence to a treatment regimen that included indinavir, were given ritonavir and saquinavir plus one or two nucleoside reverse transcriptase inhibitors. In this retrospective analysis, approximately two-thirds had plasma HIV RNA less than 400 copies/mL at 24 weeks. The data suggested a better chance of response if therapy was changed early after failure and at lower viral loads. (Abstract 427.)
Some patients apparently failing protease inhibitor therapy exhibit a persistent elevation of CD4+ lymphocyte count in the face of a rising viral load. (Abstract 419.) This may be the consequence of mutations in the protease cleavage site which may partially compensate for loss of protease inhibitor-associated resistance loss of viral fitness. (Abstract 402.) It has been suggested that, in a patient failing protease inhibitor therapy who has no remaining alternatives, continued administration of the failing protease inhibitor may still provide benefit.
Reduced intensity maintenance therapy
Two studies examined a strategy of changing to maintenance therapy with fewer drugs after a successful period of multi-drug induction therapy. In the TRILEGE study, previously antiretroviral patients with CD4 counts less than 600 cells/mm3 who had plasma HIV RNA less than 500 copies/mL after three months of therapy with ZDV, 3TC, and indinavir were randomized to continue maintenance therapy with either all three drugs, ZDV plus 3TC, or ZDV plus indinavir. Six months after randomization, the incidence of increase in plasma HIV RNA to less than 500 copies/mL was 10% in the three-drug maintenance regimen, 38% in those on ZDV plus 3TC, and 24% in those on ZDV plus indinavir (P < 0.001). These results led to premature discontinuation of the study by the data safety monitoring board. (Abstract LB15.)In ACTG 343, 509 subjects with no prior protease inhibitor or 3TC therapy, more than 200 CD4 cells/mm3 and, more than 1000 HIV RNA copies/mL of plasma were treated with ZDV, 3TC, and indinavir for 24 weeks. Three hundred nine patients who had plasma HIV RNA less than 200 copies/mL at that time were randomized to maintenance therapy with all three drugs, ZDV plus 3TC, or indinavir alone. The incidence of virologic failure (2 consecutive plasma HIV RNA measurements > 200 copies/mL during maintenance) was 3% in the three-drug maintenance group, 18% in those receiving two drugs, and 16% in those receiving indinavir alone. (Abstract LB16.)
Thus, in each investigation, reduced intensity maintenance antiretroviral
therapy was associated with an unacceptable failure rate-a not unpredictable
result. I am aware that there has been great concern about the safety of
the design of ACTG 343. As with the patients who failed monotherapy with
amprenavir (see above), I look forward to future information concerning
the outcomes of the 16% of patients randomized to maintenance therapy with
indinavir alone in ACTG 343.
Metabolic Changes During Antiretroviral Therapy
Three men and one woman, all receiving indinavir, developed multiple symmetrical lipomatosis first recognized after a median of six months of protease inhibitor therapy. All four developed dorsocervical fat pad enlargement (buffalo hump) and the woman also had an increase in breast size and abdominal girth. One had hyperglycemia, and two had mild hypertriglyceridemia. Dexamethasone suppression tests were normal. (Abstract 407.) A cervical fat pad removed from one patient revealed nonencapsulated mature fat tissue. (Abstract 411.)
Seven men, age 39-61 years, were found to have dorsocervical fat pad enlargement. Only three were receiving a protease inhibitor. None had biochemical evidence of Cushing's syndrome. Compared to matched HIV-infected controls, cases had essentially the same proportion of total body weight as fat (17.4% vs 17.5%), but significantly greater truncal fat as a proportion of total body fat (64.7% vs 55.6%). Cases also had increased triglyceride but normal cholesterol. ( Abstract 409.)
Five (7%) of 72 patients receiving protease inhibitor therapy in one practice developed "protease paunch," first detected after a median of 18 months of therapy. Their median age was 46 years, and they had a median CD4+ lymphocyte count of 195 cells/mm3 and a median viral load of 9132 copies/mL. Three of the five patients were men; one of the two women was postmenopausal, and the other had regular menses. One patient had hyperglycemia. All had normal random serum cortisol, normal somatomedin-C, and low normal growth hormone concentrations. One patient was hypothyroid. In one woman, FSH, LH, testosterone, DHEA sulfate, androstenedione, and prolactin concentrations were normal. (Abstract 408.)
The amount of visceral adipose tissue was assessed in 37 HIV-infected patients, including 13 not receiving indinavir, 14 who had received indinavir for more than six months but who had no abdominal complaints, and 10 who had also received indinavir for more than six months but who complained of abdominal distention and fullness. Computerized tomography was performed for assessment of total abdominal adipose tissue (TAT) and visceral adipose tissue (VAT) on a single cut at the L4/L5 level. Although there was no significant difference between groups in body mass index, the mean VAT/TAT ratios for the three groups were, respectively, 0.44, 0.60, and 0.73 (P = 0.008), indicating significant increase in visceral fat in some patients recieving indinavir. The VAT/TAT ratio correlated modestly with serum cholesterol and with serum triglyceride. (Abstract 413.)
Asymptomatic HIV-infected patients receiving protease inhibitor therapy (n = 116) or controls who were naïve to this class of drugs (n = 32) were evaluated. Seventy-two (64%) of those receiving protease inhibitor therapy developed lipodystrophy, defined as fat wasting of the face and limbs with relative central adiposity, after a mean of 10 months. Lipodystrophy in these patients was associated with a mean weight loss of 0.51 kg per month and a mean fat loss of 5.5 kg in all regions except the abdomen, relative to the control group. Three (2%) developed new or worsened diabetes mellitus. Patients with lipodystrophy had significantly higher triglyceride, cholesterol, insulin, and C-peptide levels, as well as higher insulin resistance scores. Lipodystrophy was more severe and developed sooner in patients receiving ritonavir-saquinavir than in those receiving indinavir. (Abstract 410.)
Forty patients, some already receiving stable therapy and others before and after starting antiretroviral therapy, were evaluated prospectively. Sixteen patients started a protease inhibitor as part of their regimen, eight started 3TC; 16 patients were on stable therapy not containing a protease inhibitor or 3TC or on no therapy. After a median follow-up of approximately four months, glucose, triglyceride, cholesterol, and insulin levels increased significantly only in the protease inhibitor group. Testosterone, DHEA, and cortisol levels did not change in any group. There were no significant changes in total or regional fat or lean body mass as determined by dual-energy X-ray absorptiometry. (Abstract 414.) Thus, in this four-month study, alterations in fat distribution could be detected in a small number of patients.
During 1150 person-months of observation, four (1.4%) of 290 patients developed marked (> 200 mg/dL) increases in serum glucose, and two of these developed ketoacidosis. The calculated incidence was 0.35 per 100 person-months for severe hyperglycemia and 0.52 for any hyperglycemia. The median time from start of protease inhibitor therapy was 53 days (range, 22-230 days). Protease inhibitors being taken at the time of increase in blood glucose included ritonavir, saquinavir, and indinavir. (Abstract 415.)
These studies describe metabolic changes, largely consisting of hypertriglyceridemia, insulin resistance and, infrequently, hyperglycemia, as well as alterations of adipose tissue distribution in patients mostly receiving protease inhibitor therapy. The abnormal fat tissue distribution is not the result of increased general body fat accumulation, but rather presumably represents regional abnormalities of lipolysis and fat storage. The mechanism(s) is not known but may be related to the observation described in Abstract 410 that the 12 amino acids spanning the HIV protease catalytic site have 70% homology with the low-density lipoprotein receptor-like protein, a hepatic scavenger of circulating lipids. It can be hypothesized that protease inhibitors may also interfere with the function of this protein.
The incidence of the development of diabetes mellitus while receiving
protease inhibitor therapy is low. It is hoped that the risk does not increase
cumulatively with prolonged antiretroviral therapy.
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