HIV-Infected Patients
Total Page：16
File Type：pdf, Size：1020Kb
New Drugs for the Treatment-Experienced Patient Joseph Eron, md Associate Professor of Medicine and Director, Clinical Core unc Center for aids Research, University of North Carolina at Chapel Hill Summary by Tim Horn Edited by Jay Dobkin, md; Michael Saag, md reatment options for antiretro- humans by adenosine deaminase into D- Deeks and his colleagues in 1998 demon- viral-experienced patients leave a dioxolane guanine (dxg), a metabolite that strated a 1 log reduction in hiv-rna in hiv- lot to be desired. According to Dr. has potent activity against hiv and hbv. infected patients—more than 50% of whom Joe Eron, patients who have treat- According to in vitro data presented at were treatment-experienced—who received ment experience in all three classes the 3rd International Workshop on hiv tenofovir df 300 mg once daily as of currently available antiretrovi- Drug Resistance and Treatment Strategies, monotherapy for 28 days (Deeks, 1998). Trals have, at best, a 30% chance of re- held in June 1999, dapd was found to in- According to in vitro data presented by ducing their viral load to levels below 400 hibit wild-type and mutant isolates resistant Gilead’s Dr. Michael Miller at the recent copies/mL upon initiating a salvage regi- to azt (Retrovir) and 3TC (Borroto-Esoda, 4th International Resistance Workshop, the men. Cross-resistance within each class of 1999). The drug was also reported to be ac- resistance pattern for tenofovir df is simi- drugs, particularly the protease inhibitors tive against strains collected from patients lar to that of its chemical predecessor adefo- (pis) and non-nucleoside reverse tran- who have failed various nrti and nnrti vir, a compound no longer in development scriptase inhibitors (nnrtis), essentially combination therapies, including those for the treatment of hiv (Miller, 2000). Low- hobbles the effectiveness of switching ther- with variants harboring the multi-nrti-re- level resistance to tenofovir df is mediated apies in the face of virologic failure. sistant mutations Q151M and T69SS. by the K65R mutation. Of particular interest, It goes without saying that new anti- As for its own resistance profile, in though, is the finding that the M184V muta- retrovirals are definitely needed—drugs vitro data indicate that dapd selects for tion associated with 3TC resistance may in- that have potent and durable efficacy pro- the L74V and K65R mutations that are as- crease hiv sensitivity to the drug. hiv har- files for patients with both limited and ex- sociated with fourfold and eightfold in- boring the multi-nrti-resistance mutation tensive antiretroviral experience. creases in the drug’s IC50, respectively. Q151M remained susceptible to tenofovir df, For the sake of tailoring his talk to focus These mutations may confer at least some but mutations at codon position T69SS— exclusively on new drugs in development cross-resistance to ddI and ddC. which can also induce high-level cross- for antiretroviral-experienced patients, Dr. More recently, in a pilot study conduct- class resistance—were associated with de- Eron excluded several compounds in de- ed by Dr. Steven Deeks and his colleagues, creased tenofovir df sensitivity. velopment. Among these were the nucleo- 20 treatment-experienced patients received At the 39th Interscience Conference on side reverse transcriptase inhibitor (nrti) oral doses of 200 mg, 300 mg, or 500 mg Antimicrobial Agents and Chemotherapy emtricitabine (ftc); the nnrti emivirine twice daily of dapd monotherapy (Deeks, (icaac) last fall in San Francisco, Dr. Robert (MKC-442); and the protease inhibitors DMP- 2000). All patients had previously failed Schooley presented preliminary 24-week 450 and GW-433908, an amprenavir (Agen- an average of seven antiretroviral drugs data from a placebo-controlled study com- erase) prodrug. “These drugs are all very and had been treated for an average of paring three doses of tenofovir df—75 similar to compounds we now currently four years. After 15 days of therapy, the re- mg, 150 mg, and 300 mg given once dai- have,” explained Dr. Eron. “While each duction in hiv-rna ranged from 0.5 to 1.1 ly—added to a stable, yet failing anti- drug may have an advantage over current log. Data correlating genotype or phenotype drugs, these benefits, which include bet- to virologic response to dapd were not pre- Chemical Name: dapd ter dosing schedules, will likely be enjoyed sented by Dr. Deeks. All doses were gen- Generic Name: n/a only by antiretroviral-naive patients. For- erally well tolerated, and the pharmacoki- tunately, there are still quite a few drugs left netics data generated thus far may support Brand Name: n/a to discuss, many of which stand to help a once-daily dosing schedule. Sponsor: Triangle Pharmaceuticals those who need them most.” Dosing: Twice daily in early studies; once-daily dosing possible. Tenofovir Disoproxil Fumarate Development Phase: Phase I/II (Bis[POC] PMPA; GS-902) I. New Nucleoside/ tenofovir df is gilead science’s second Resistance Profile: Selects for the L74V adenosine nucleotide analogue and is an and K65R (in vitro); may confer some Nucleotide Analogues cross-resistance to ddI and ddC; oral prodrug of pmpa. In vitro, it has potent appears active against variants with Diaminopurine Dioxalane (DAPD) activity against hiv, siv and Moloney- Q151M and T69SS mutations (in vitro). dapd is being developed by triangle murine sarcoma virus at doses several Pharmaceuticals. It is a novel dioxolane hundred times less than those toxic to cells. Safety Profile: “Generally well tolerat- ed” in pilot study (Deeks, 2000). purine nrti that is rapidly converted in Preliminary data presented by Dr. Steven 10 THE PRN NOTEBOOK™ • VOLUME 5, NUMBER 3 • SEPTEMBER 2000 • WWW.PRN.ORG also decreased susceptibility to capravirine ty and efficacy in antiretroviral-naive pa- Chemical Name: Bis(poc) pmpa by 13-fold (Potts, 1999). tients can be found in “Treatment Strate- Generic Name: Tenofovir The dose of capravirine will likely be gies for the Antiretroviral-Naive Patient,” 1400 mg taken twice daily, based on pos- beginning on page 4]. Brand Name: n/a itive results using this and a lower dose in In terms of its resistance profile, Sponsor: Gilead Sciences a recent 10-day clinical trial; 1400 mg bid lopinavir was specifically developed to be Dosing: 300 mg once daily was associated with a >1 log drop in an- active against isolates that contain muta- Development Phase: Phase II tiretroviral-naive patients (Hernandez, tions at position V82 of the protease en- 2000). “This may seem like a large dose,” zyme. A substitution at position V82 is Resistance Profile: Selects for the K65R Dr. Eron explained to a number of raised known to be a primary mutation associat- mutation (in vitro); may confer some eyebrows in the room. “However, Agouron ed with resistance to ritonavir, indinavir, cross-resistance with ddI and ddC; is currently developing the drug using 700 and possibly saquinavir. Other mutations, variants with M184V appear hypersensi- tive to tenofovir; tenofovir active mg tablets, which translates into two pills including M46I/L (a primary mutation asso- against variants with Q151M mutation; twice a day.” With respect to actual data in ciated with indinavir resistance) and I84V (a variants with T69SS mutation less antiretroviral-experienced patients, Dr. secondary mutation reported among all sensitive to tenofovir. Eron noted that, “phase III studies looking currently available protease inhibitors) can Safety Profile: “No serious toxicities;” at this drug in experienced patients are ex- be selected by in vitro passage of virus in no nephrotoxicity reported pected to begin enrollment soon. We the presence of the drug (Mo, 1999). (Schooley, 1999). haven’t seen much of anything yet, but Seventy-two week data from Abbott’s this is certainly one to watch.” M97-765 study—a trial evaluating lopinavir in retroviral regimen (Schooley, 1999). Most patients who had failed one protease in- patients enrolled in the study had been hibitor-based regimen—were presented at receiving antiretroviral therapy for at least DPC-961 the 13th International aids Conference four years and a significant percentage— DPC-961 is a new nnrti being developed by (Thompson, 2000). A quick glimpse at the almost 94%—carried variants resistant to DuPont Pharmaceuticals. According to the 72-week data is provided in Figure 1. azt, 3TC, or both; more than 60% had mu- manufacturer, the half-life of DPC-961 is a In the study, 70 patients were treated tant hiv conferring resistance to at least whopping 140 hours, a finding that will with lopinavir monotherapy for two weeks; one protease inhibitor. At the 300 mg lead to a most favorable dosing schedule. nevirapine (Viramune) and at least one dose, hiv-rna decreased by approximate- The drug also has three- to eightfold greater nrti were then added to complete the new ly 0.75 log, a benefit that proved durable potency against K103N-containing isolates regimen. Approximately two-thirds of all for at least 24 weeks. Of note, no serious and robust activity against variants with patients had a greater than fourfold de- toxicities were reported; nephrotoxicity single substitutions such as Y181C and V106A. crease in susceptibility to one currently similar to that seen in patients receiving “Development of DPC-961 has slowed available protease inhibitor, most notably adefovir was not observed in this study of down,” commented Dr. Eron. “We’re not ex- the pi taken prior to enrollment in the patients receiving tenofovir df. actly sure what’s going on, and this is not to lopinavir study; one-third of the patients “The data from this study really look say the drug will not eventually move for- had a greater than fourfold decrease in sus- promising,” commented Dr. Eron. “But, ward, but trials may begin enrolling soon.” ceptibility to three currently available pis.