New drugs for HIV therapy (2002)

Introduction Despite the availability of 16 antiretroviral drugs approved for the treatment of HIV infection, issues of adherence, toxicity, antiretroviral activity and drug resistance continue to complicate combination antiretroviral therapy. Consequently, there is a need for new antiretroviral agents that can improve convenience, reduce toxicity, improve antiretroviral activity against both wild type and drug resistant HIV, penetrate tissue reservoirs (e.g., genital tract, central nervous system), and exploit new targets in the life cycle of HIV. There are a number of antiretroviral drugs in development (Table 1) both in existing classes of agents: nucleoside analogue reverse transcriptase inhibitors (nRTI), nucleotide RTI (ntRTI), non-nucleoside RTI (NNRTI), and protease inhibitors (PI); and drugs with new mechanisms of action: entry inhibitors and integrase inhibitors.Table 1: Investigational antiretroviral drugs (partial list).HIV reverse transcriptase inhibitors Nucleoside reverse transcriptase inhibitors (nRTIs) Emtricitabine (FTC) Emtricitabine (FTC) is an investigational cytosine nRTI that is active against HIV-1 and hepatitis B virus [1]. The pharmacokinetic profile allows once-daily dosing [2]. The in vitro activity is approximately 5-fold greater than that of lamivudine (3TC) [3,4], but the reverse transcriptase (RT) M184V mutation confers resistance to both FTC and 3TC. In the ANRS 091 clinical trial, FTC was combined with ddI and EFV as a once-daily regimen in 40 treatment-naïve patients [5]. In an intent-to-treat analysis of the 96-week follow-up data, 85% of the patients maintained a plasma viral load < 400 copies/ml (cpm), and 80% had < 50 cpm. CD4 cell count increased by a median of 259 cells/mm3. The most common adverse events were central nervous system symptoms, diarrhea, rash, hypertriglyceridemia and elevated hepatic transaminases. In a pharmacokinetic substudy, the combination of FTC, didanosine, and efavirenz did not demonstrate significant drug interactions [2]. In study FTC-303, 294 patients switched from a 3TC-containing regimen to an FTC-containing regimen [3]. At week 48,227 (77%) had HIV-1 RNA < 400 cpm. A total of 214 of these 227 elected to continue into study FTC-350. On that study, 179 patients maintained suppression < 400 cpm and 157 patients had < 50 cpm through week 72. In FTC-303 and FTC-302, discontinuations and treatment-related grade 3/4 laboratory abnormalities were comparable for both FTC and 3TC [6]. In study FTC-302, drug-naive patients were randomized to receive either FTC or 3TC in combination with stavudine and nevirapine. Following five deaths and a higher than normal incidence of hepatotoxicity, the study halted enrollment of new patients. It was later determined that the cause of the fatalities and liver toxicities was most likely not caused by FTC. A genotype sub-study was performed in 47 patients in FTC-302 who were experiencing virologic failure [7]. Of 32 patients with at least 1 detectable mutation, the incidence rate was 57% in the FTC arm and 88% in the 3TC arm. The incidence of the M184V was 17% in the FTC group vs. 59% (p < 0.1) in the 3TC group. It may be that the M184V mutation emerges slower under FTC than under 3TC selective pressure. The clinical significance of the delayed selection of the M184V mutation is not yet clear. FTC-301 is an ongoing 48-week study comparing FTC 200 mg once daily with stavudine (d4T) twice daily, each in combination with didanosine and efavirenz [8]. A total of 571 patients were enrolled, with a baseline mean plasma HIV-RNA level of 4.9 log10 cpm and a mean CD4 count of 288 cells/mm3. At week 24, the FTC arm demonstrated 87% of the patients had HIV RNA levels less than 400 cpm and 81% had levels less than 50 cpm, compared to 79% and 70%, respectively, in the stavudine arm (p = 0.02). The percentage of subjects with virologic failure was lower in the FTC arm (4%), compared with the stavudine arm (10%, p = 0.01). CD4 cell counts increased 156 cells/mm3 over baseline in the FTC arm, compared to 119 cells/mm3 in the stavudine arm. MIV-310 (FLT, alovudine) MIV-310 (FLT, alovudine) is a 3’-fluoro-substituted thymidine analogue structurally related to zidovudine that may prove effective against viral isolates resistant to nucleoside analogues. A 4-week phase II study enrolled 15 patients who were experiencing failure on an NRTI-containing regimen and had at least 2 thymidine-associated mutations (TAMs) as demonstrated by genotypic resistance testing [9]. MIV-310 7.5 mg once daily was added to the patients’ stable antiretroviral regimens. At baseline, the patients had a median of 4 TAMs, 6 NRTI mutations (100% of strains with T215Y/F), an HIV RNA level of 3.93 log10 cpm and CD4 cell count of 360 cells/mm3. The week 4 analysis showed a significant reduction in HIV RNA level from baseline in MIV-310 without stavudine regimens (-1.88 log), compared to MIV-310 with stavudine regimens (-0.57 log), as well as an increase in CD4 cells. MIV-310 was well tolerated with no serious adverse events reported. In addition, no drug resistance developed during the follow-up period. Further studies will be needed to determine proper dosage and establish long-term safety, including hematologic and hepatic effects. SPD-756 (formerly BCH-13520) In vitro resistance testing of this new heterosubstituted purine analogue suggests that this drug may have activity in patients with HIV-1 variants resistant to zidovudine (ZDV) or 3TC [10]. In vitro 50% inhibitory concentrations (IC50) ranged between 0.14–0.63μM against wild type virus strains. Variants with ZDV and ZDV/3TC resistance were susceptible to SPD-756 in clinical isolate testing. 3TC-resistant strains showed only a slight reduction in susceptibility. Susceptibility was reduced in variants with the 69 insertion or Q151M complex of the reverse transcriptase. SPD-756 selects for mutations in vitro at codon V751, then later switches to K65R. Drug resistance to SPD-756 emerged slowly in vitro and the selected variants have a low level of resistance (1.3–3.6 fold). Low cellular and mitochondrial toxicity in vitro was observed [11]. Single dose pharmokinetics from a phase I dose-escalation study (100 to 1200 mg) in 38 healthy seronegative men demonstrated that SPD-756 was absorbed well orally and reached drug concentrations that were significantly higher than the in vitro IC50 that may be sufficient to suppress viral replication in vivo [12]. Nucleotide reverse transcriptase inhibitors (ntRTI) GS 7340 GS 7340 is a novel oral prodrug of tenofovir [13]. In contrast to the approved oral prodrug tenofovir disoproxil fumarate (TDF), GS 7340 is stable in plasma and is selectively converted to tenofovir inside peripheral blood mononuclear cells (PBMCs). Following its oral administration to dogs and rhesus monkeys, the bioavailability of tenofovir was approximately 20%. Compared to TDF, > 38-fold higher levels of tenofovir were detected in animal PBMCs after a single oral dose of GS 7340. Efficient accumulation in lymphoid tissue was also observed after 24 hours. In vitro GS 7340 was at least 5-fold and 500-fold more potent than TDF and tenofovir, respectively. The 50% effective concentration (EC50) was approximately 5 nM for HIV and 10 nM for hepatitis B virus. The increased intracellular concentrations of GS 7340 may be important for suppressing ongoing viral replication in long-lived CD4 cells. Phase 1 studies are in progress. Non-nucleoside reverse transcriptase inhibitors (NNRTI) DPC 083 DPC 083 (BMS 56,1390) is an investigational NNRTI that is structurally very similar to efavirenz. In vitro it had equivalent potency to efavirenz against wild-type virus but increased potency against site-directed HIV strains containing the key RT resistance mutations K103N, K101E and G190S. The results of early phase II studies suggest that the drug may be active in treatment naïve patients, and most importantly, in patients with NNRTI-resistant virus. In the phase II study DPC 083–203, patients who experienced virologic failure on a previous NNRTI-regimen were randomized to receive either 100 or 200 mg of DPC 083 once daily in combination with 2 nRTIs [14]. At baseline, 61% and 39% had failed nevirapine and efavirenz regimens, respectively. A total of 94% of the patients had mutations consistent with NNRTI resistance including mutations at reverse transcriptase positions 101, 103, 181, and 190. In the on-treatment analysis of both arms combined at week 8, the response rate (< 400 cpm) was 57%; the mean change in viral load from baseline showed a decrease of 1.28 log10 cpm. Response rates appeared to be higher when at least 1 new nRTI was changed at baseline: 40% [4/10 patients] who did not change nRTIs, 72% [10/15] with 1 new nRTI, and 67% [10/15] with 2 new nRTIs responded. In a study in treatment-naïve individuals (DPC 083–201), three once-daily doses of 50, 100 or 200 mg of DPC 083 were compared to efavirenz [15]. In an intent-to-treat analysis at week 16, response rates were similar for all arms: 60–70% achieved viral load levels < 50 cpm. Premature discontinuation rates were highest in the 200 mg dose, as was the occurrence of rash. The dose-related rash was reported to resolve quickly when the drug was discontinued although the half-life of DPC 083 is approximately 5 days. The incidence of dizziness was less frequent than with efavirenz. The preliminary results of these studies suggest that DPC 083 may have less neurotoxicity compared to efavirenz, while still being active in virologic failure against NNRTI-resistant viruses. TMC 125 TMC 125 is an investigational diaminopyrimidine NNRTI. In small proof of concept studies it demonstrated high potency in both treatment-naive and -experienced patients. In vitro experiments demonstrated potent activity with inhibition of 98% of recombinant HIV-1 clinical isolates and 94%, 96% and 97% of isolates resistant to efavirenz, delavirdine and nevirapine with IC50 values of less than 100 nM. In contrast to approved NNRTIs, at least two substitutions in the RT gene are required for resistance to develop [16,17]. In a monotherapy trial in treatment-naïve patients, plasma HIV RNA decreased after 1 week in a similar initial rate of decline as therapy with a 5-drug antiretroviral regimen [18]. Monotherapy with a 900 mg bid dose demonstrated, after 7 days, a mean change in viral load level of-1.99 log10 cpm from baseline, compared to the placebo group with a change of -0.05 log10 cpm (p < 0.001) [19,20]. A phase IIA study of 16 treatment-experienced patients who were failing an efavirenz- or nevirapine-containing regimen, changed the NNRTI to TMC 125 without changing the other background antiretroviral therapy [21,22]. Median HIV RNA level was 10 753 cpm at baseline. On the TMC 125 regimen, 12 patients had a least a 0.5 log10 cpm decrease in HIV RNA level, while 7 had at least a 1.0 log10 cpm decrease. At baseline, NNRTI mutations included the L100I, K103N, Y181C, and G190A/S, with 12 of 16 patients having multiple NNRTI mutations. There was no evidence of the development of resistance at the end of the 7-day period. TMC 125 was well tolerated during this study. In pharmacokinetic studies, peak concentrations occurred 2–4 hours post-dose and the mean elimination half-life was 30–40 hours [23]. Steady state was achieved in 7 days and TMC 125 did not induce or inhibit its own metabolism. Administration with food increased the oral bioavailability approximately 3-fold. A pharmacokinetic study of 30 healthy seronegative men investigated lopinavir/ritonavir 400/100 mg twice daily in combination with TMC 125 and found that the concentrations of both drugs were not changed by coadministration [24]. A second study showed that full doses of ritonavir, efavirenz, and nevirapine all decreased TMC125 levels (AUC decreased 46–55%, Cmax decreased 32–36%), while indinavir increased TMC 125 levels (AUC and Cmax increased 51%). TMC 125 decreased indinavir and saquinavir levels (AUC decreased 46–52%, Cmax decreased 28–46%) [25]. HIV protease inhibitors Atazanavir (BMS-232,632) Atazanavir (BMS-232,632) is an investigational azapeptide protease inhibitor with in vitro activity against both wild type virus and some viral variants with PI-associated mutations [26,27]. In one study, of 9 treatmentnaïve subjects who experienced virologic failure on an atazanavir-containing regimen, 8 developed a unique I50L substitution in the protease gene and this was associated with increased in vitro susceptibility to other protease inhibitors [28]. However, several studies also showed that in subjects previously treated with protease inhibitors who went on to take atazanavir-containing regimens and then experienced virologic failure, crossresistance among the protease inhibitors occurred commonly [28,29]. Pharmacokinetics support once a day dosing [30]. Recently, phase III studies in both treatment-naïve and -experienced subjects were reported: Sanne and colleagues conducted an open-label study of 464 treatment-naïve patients with HIV RNA > 2000 cpm and CD4 cells > 75–100/mm3 who were randomized to receive stavudine/lamivudine with atazanavir (400 or 600 mg qd) or nelfinavir 1250 mg twice daily [31]. At 24 weeks, 67–70% in the atazanavir groups and 63% in the nelfinavir group had HIV RNA < 400 cpm. Doseproportional grade 3–4 hyperbilirubinemia (without hepatic transaminase increases) requiring dose reduction of atazanavir occurred in 5% of subjects taking 400 mg qd and 10% taking 600 mg qd. Serum lipid levels increased significantly in the nelfinavir group compared with the atazanavir group [32]. Squires and colleagues reported a double-blind study of 805 treatment-naïve subjects with baseline HIV RNA ˜70 000 cpm and CD4 ˜320 cells/mm3 who received zidovudine/lamivudine twice daily in combination with either atazanavir 400 mg or efavirenz 600 mg once a day [33]. At 24 weeks, virologic responses were not different statistically between the two arms with 72% and 26% (atazanavir) and 69% and 31% (efavirenz) with HIV RNA levels < 400 and < 50 cpm, respectively. Lipid levels were stable or decreased in the atazanavir group, compared with increases from baseline LDL (+18%) and triglycerides (+16%) observed in the efavirenz group. Haas and colleagues presented a blinded study of 85 subjects with virologic failure on a prior PI-containing regimen with HIV RNA 1000–100 000 cpm and CD4 >= 100 cells/mm3, randomized to receive 2 NRTIs with atazanavir (400 or 600 mg)/saquinavir 1200 mg qd or ritonavir 400 mg/saquinavir 400 mg twice daily [34]. At 48 weeks, the mean change from baseline HIV RNA was -1.2–1.4 log10 cpm (atazanavir/saquinavir groups) vs. -1.7 log10 cpm (ritonavir/saquinavir group). In addition, serum lipid levels decreased in the atazanavir groups, but increased in the ritonavir group. An expanded for atazanavir is is an investigational with serum levels increased by coadministration with ritonavir In demonstrated antiretroviral activity in viral isolates with resistance to other and colleagues reported results from an open-label study of subjects who had experienced virologic failure RNA > cpm) on PI-containing regimen nelfinavir or and were randomized to receive 2 NRTIs with dosing of or 1250 100 mg or saquinavir 400 400 mg At 16 weeks, median in HIV RNA from baseline were log10 cpm log10 cpm 1250 mg) and log10 cpm and the with HIV RNA levels < 400 and < 50 cpm were 39% and and 1250 mg) and 40% and respectively. occurred more commonly with the higher dose of and colleagues reported the results from an open-label study of 69 subjects experiencing virologic failure on second regimen with HIV RNA >= cpm who were randomized to receive or 100 mg At baseline, viral isolates had decreased susceptibility 4 to a mean of At 48 in the group, the mean change in HIV RNA was log10 cpm for subjects with 5 PI-associated resistance mutations vs. log10 cpm with > 5 mutations. the study, 6 subjects developed decreased susceptibility to with a mean of 16 substitutions substitutions at protease positions or 1 developed resistance to and colleagues reported the results of a study of subjects who received efavirenz and one new nucleoside analogue the median change in HIV RNA was log10 cpm at 48 In an subjects were by the number of mutations at baseline and the HIV RNA decrease at 48 subjects with mutations had a log10 cpm subjects with mutations had a log10 cpm decrease and 8 subjects with mutations had a -1.7 log10 cpm decrease. At the the median IC50 change for was and The that more than 15 mutations may be required for significant reduced susceptibility to Phase III studies are TMC TMC is an investigational that is an analogue of TMC a In the selection of TMC virus occurred slowly and TMC demonstrated activity against viral some with resistance to and colleagues reported the study of TMC in healthy who received single doses mg) At low plasma concentrations increased more than to dose, but no increases were observed mg doses and plasma levels the IC50 for related to the was at higher in subjects are in progress. HIV entry inhibitors The in the life cycle of HIV is viral a with three to the CD4 cell to the or and of the viral and cell entry inhibitors are to each of these CD4 and inhibitors CD4 inhibitors a of CD4 is an of CD4 and and an investigational CD4 The HIV viral isolates in vitro and showed activity in animal reported a phase I study of in who discontinued other antiretroviral therapy for >= 4 In this dose-escalation study, of subjects were treated with one of at doses of and 10 was well serum concentrations at the highest dose the for approximately one and in HIV RNA were and colleagues single and multiple doses of in in a phase study In the arm 6 received 4 doses of 4 of 6 demonstrated in HIV RNA of > log10 cpm and had through days after of Further studies are in progress. A CD4 is a that and demonstrated antiretroviral activity in vitro against isolates of HIV, including variants resistant to RTI and In vitro resistance to is by substitutions the CD4 to but isolates susceptibility to other classes of studies are inhibitors is a inhibitor of the that demonstrated inhibition in vitro of both and in cells not with HIV Despite being well tolerated in healthy the was associated with and in some and failed to demonstrate a >= 1 log10 cpm decrease in HIV RNA levels of the for HIV was is an investigational of with potent antiretroviral activity in vitro and in animal The is orally with a serum half-life of hours that twice daily In the development of resistance to was not by a to the in healthy the and of single doses to 600 mg and days of dosing with 400 mg and was at the highest doses in both studies The study in subjects enrolled 12 subjects not taking other antiretroviral agents with CD4 > cells/mm3 who mg or 50 mg 12 hours for 10 days The drug was well tolerated and the median decrease in HIV RNA from baseline was log10 cpm mg and log10 cpm mg group). Further study at higher doses is in progress. a structurally to demonstrated greater antiretroviral activity in vitro and is in early clinical development is a that to the but not and potent antiretroviral activity in vitro and in animal studies are HIV inhibitors is an investigational HIV inhibitor that to a of the and HIV replication in vitro a the drug In with reduced susceptibility to have in the associated with a of viral of 10% reported the results of a phase I study in patients and showed in HIV RNA levels over days, with a median log10 cpm decrease at 100 mg bid to studies, including a study that enrolled treatment-experienced subjects were who had a median of 10 antiretroviral drugs and had a median baseline HIV RNA 000 cpm and CD4 cells/mm3 regimens of antiretroviral drugs selected with genotypic testing 50 mg At 48 weeks, of had an HIV RNA level decreased by >= 1 log10 or to < 400 cpm. The most commonly observed was a 87% of subjects that drug was or not and 94% continue therapy and colleagues patients randomized to efavirenz or 100 mg for 48 The change in HIV RNA from baseline was log10 cpm without and log10 cpm in the group, and 7 of and 24 of had HIV RNA < 50 cpm, respectively. occurred in of subjects most were of or and only subjects discontinued of the Phase III studies of were reported was a study of treatment-experienced subjects who had an of 12 prior antiretroviral 80% of who demonstrated 5 or more resistance mutations to the antiretroviral classes with baseline HIV RNA of 000 cpm and CD4 cells/mm3 were randomized to take regimens on genotypic and resistance with or without mg The found a greater reduction in HIV RNA at 24 in who added to background regimen vs. log10 cpm, p < with 10% study in each group. 2 a similar in subjects and demonstrated comparable virologic responses at 24 An expanded for in the is a from a of from and that is under study as an investigational HIV In is more active than and support or In demonstrated potent antiretroviral activity against viral isolates with resistance to existing classes of antiretroviral most isolates of and against both and viral isolates a the and colleagues presented the results of a phase I study in treatment-experienced subjects antiretroviral therapy with median baseline HIV RNA 000 cpm and CD4 who received as a single at total daily doses from mg to 200 mg were as were HIV RNA from log10 cpm to log10 cpm were reported in 57% of subjects and three serious adverse events related to study drug an with a and resistance to other drug classes did not virologic response In some of HIV entry inhibitors are and clinical studies are HIV integrase inhibitors by HIV of of the viral of the viral and viral is to cellular HIV integrase inhibitors are in and colleagues > 000 and a of inhibitors with a group (e.g., and that the of also selected for mutations in the integrase However, the group presented to clinical a number of were performed and new were that antiretroviral and demonstrated 1 to > 4 log10 cpm in viral load levels in a with of CD4 cell counts studies in subjects is an investigational integrase inhibitor that showed potent in vitro inhibition of HIV with an IC50 of nM In a cellular the demonstrated an of 200 nM and an of nM. In selected resistance with substitutions to the active of the integrase demonstrated antiretroviral activity both in vitro against a of clinical including resistant and in a The drug is orally and pharmacokinetic studies in healthy were reported The studies in are in progress. antiretroviral drugs are needed to improve convenience, reduce toxicity and activity against both wild-type and drug resistant viruses. A number of are in development both in existing classes transcriptase protease and classes integrase in antiretroviral therapy will from and clinical