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Historical and Current Investigational Therapies for HIV and/or Other Viral Diseases |
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Immunomodulator Therapies
Investigational |
|
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interleukin-2
(IL-2) [Proleukin] |
Expensive ($500/dose x 10 doses/cycle x 3-4 cycles per year), parenteral, and potentially toxic cytokine therapy which reliably raises CD4-counts in persons on fully-suppressive HAART: the clinical significance of these laboratory observations is under investigation. |
|
therapeutic
vaccination [Remune and others] |
Under investigation; minimal laboratory indicators of improved immunity are being evaluated for clinical significance |
| interferon | Expensive, parenteral, and toxic therapy of unproven benefit: recent studies indicate interferon may have moderate activity against HIV at 5 million units injected SQ daily. Interferon therapy is approved and useful for Kaposi’s sarcoma and HCV. It may also be useful against severe HPV. |
| Other Investigational Therapies | ||
| Antiretroviral Therapy for HIV Infection | ||
|
Therapy |
Mechanism
|
Status, Adverse Effects, & Other Information |
| Capavirine | NNRTI | May be able to overcome resistance (K103N)
to prior NNRTI therapy. Recent studies show day 15 median (mean) HIV-1
load decreased by 1.34 (1.45) log(10) copies/mL in patients receiving 25
mg/kg/day.4 Capravirine, a new nonnucleoside reverse transcriptase inhibitor (NNRTI), failed to control HIV better than placebo in a 48-week study of people with resistance to NNRTIs, according to a report at the 12th Conference on Retroviruses and Opportunistic Infections held in Boston, Massachusetts. However, a subgroup analysis suggested that a regimen including capravirine, nelfinavir, and two nucleoside reverse transcriptase inhibitors (NRTIs) had some activity against virus resistant to both zidovudine and lamivudine. In vitro studies indicate that capravirine is able to inhibit some HIV strains resistant to current NNRTIs. Laboratory work also suggests that resistance to capravirine evolves more slowly than to other NNRTIs, Rick Pesano, MD, PhD reported. The current trial randomized people taking a failing NNRTI regimen to receive 700 mg or 1400 mg of capravirine twice daily or placebo. All participants also received twice-daily nelfinavir and two NRTIs picked on the basis of treatment history and genotype. None of the 179 study participants had been previously treated with a protease inhibitor. Trial enrollees had moderately advanced disease, with an average viral load around 4.4 log copies/mL and median CD4 counts of 206 cells/mm3 in the placebo group, 248 cells/mm3 in the 700-mg capravirine group, and 249 cells/mm3 in the 1400-mg capravirine group. Resistance to NRTIs and NNRTIs was similar across the study arms. Pesano reported 48-week failure rates—defined as failure to reduce the viral load by 0.5 log by Week 4, or rebounding after a 0.5 log reduction—of 24% with placebo, 15% with 700 mg of capravirine, and 13% with 1400 mg, differences that were not statistically significant. The reductions in viral load from baseline to Week 48 also did not differ significantly: 2.1 logs, 2.3 logs, and 2.4 logs, respectively. A 48-week noncompleter-equals-failure analysis determined that 58% of patients taking 1400 mg of capravirine twice daily had a viral load below 400 copies/mL, compared with 43% taking 700 mg twice daily, and 46% taking placebo. These differences also fell short of statistical significance. In a preplanned analysis of nonrandomized subgroups who began treatment with virus resistant to zidovudine and lamivudine, 54% in the 1400-mg group had a viral load under 400 copies/mL at Week 48, compared with 36% taking 700 mg, and 31% taking placebo. This trend was not statistically significant, however. The better noncompleter response with 1400 mg of capravirine partly reflects the high dropout rates in the other 2 arms—44% with placebo, 42% with 700 mg capravirine, and 30% with 1400 mg capravirine. Whereas 15% of patients stopped the 700-mg dose because of side effects, 7% stopped the 1400-mg dose for that reason. Diarrhea affected 65% in the 1400-mg group and 53% in the 700-mg group. However, diarrhea also was reported by 49% given placebo, and the incidence of diarrhea in all treatment arms may have been due to nelfinavir therapy. Rates of nausea were 35% with 1400 mg, 27% with 700 mg, and 20% with placebo. Dr. Pesano noted that the high failure rates in all three study arms came as a surprise, since people started nelfinavir with no protease inhibitor experience and also began carefully chosen NRTIs. The study outcomes will be further scrutinized as the development of capravirine continues. [CROI 2005: http://clinicaloptions.com/hiv/news/news_CROI2005_2.asp] |
| PA-457 |
Maturation inhibition |
In an initial study, single dose
PA-457 was given to 24 men with HIV who were either drug-naive or who had
not taken highly active antiretroviral therapy (HAART) for at least 4 weeks.
Six men each were given 75, 150, or 220 mg of the drug, or a placebo.
The 150-mg and 250-mg doses cut the median viral load roughly 3-fold (by
0.45 and 0.51 log10 copies/mL, respectively). This is a
respectable amount for a single dose of drug. Presenter David Martin
compared this with the drugs tenofovir and D-d4FC which in single-dose
studies produced median viral load reductions of 0.33 and 0.45 log10
copies/mL, respectively. The most interesting finding was that the
viral reduction appeared to be sustained for many days. PA-457 has a
half-life of 2 to 3 days, and a viral load reduction of more than 0.35 log10
copies/mL was maintained for 8 to 9 days after treatment with the 2 larger
doses. Martin announced that a 10-day study of PA-457 monotherapy is
ongoing, and phase 2 efficacy studies are planned to start toward the end of
2005. [CROI 2005:
http://clinicaloptions.com/hiv/news/news_CROI2005_16.asp] The Phase II study met its primary endpoint by demonstrating a statistically significant reduction in the level of HIV in the blood compared to placebo. The median reduction in HIV viral load in the trial was greater than 1 log10, or a 90% decrease, at the highest dose. The US Food and Drug Administration (FDA) has granted Fast Track designation to PA-457. In this randomized double-blind Phase 2a study, performed at leading academic centers in the US, PA-457 at one of four doses (25, 50, 100 or 200mg; 6 patients per group) or placebo (8 patients), was administered orally once daily for 10 days to HIV-infected subjects not on other antiretroviral therapy. The primary endpoint was viral load reduction on day 11. Other endpoints included safety, tolerability and pharmacokinetics of the drug. At the 100 and 200 mg doses, PA-457 treatment for 10 days resulted in statistically significant reductions in viral load compared to placebo, with individual decreases of up to 1.7 log10. At the 200mg dose level, the median viral load change at Day 11 was -1.03 log10. Median Day 11 values at the other dose levels were: Placebo: +0.03 log10; 25mg: +0.05 log10; 50mg: -0.17 log10; 100mg: -0.48 log10. In patients with baseline viral loads under 100,000 copies/ml the median Day 11 reduction was -1.52 log10 at the 200mg dose level (three of six patients) and -0.56 log10 at the 100mg dose level (five of six patients). Genetic analysis of HIV in patients pre- and post- treatment, available now for 21 out of 33 patients in the study, showed no evidence of the development of resistance to PA-457, the same result as seen previously in a single dose study with PA-457. All doses were observed to be generally safe and well tolerated with no Grade 3 or 4 laboratory abnormalities. All adverse experiences were mild or moderate and no dose-limiting toxicity was identified. |
| DPC 681 | PI | Active against PI-resistant HIV |
| DPC 684 | PI | Active against PI-resistant HIV |
| TMC114/r | PI | Active against multidrug
resistant HIV. After 24 weeks of treatment in triple-class-experienced HIV-infected patients, the investigational protease inhibitor (PI) TMC114 controlled resistant HIV significantly better than comparison regimens.[1] Richard Haubrich, MD, from the University of California, San Diego, reported an average viral load drop of 1.85 log copies/mL with the highest dose of TMC114 vs 0.27 log with alternative PI regimens. The findings presented by Dr. Haubrich at the 12th Conference on Retroviruses and Opportunistic Infections in Boston, Massachusetts, raised expectations that ritonavir-boosted TMC114 may be a potent option for people with multiclass resistance. At the highest dose of TMC114/ritonavir, viral loads dropped below 50 copies/mL, even in 5 of 13 people for whom resistance testing could identify no other active antiretrovirals. Researchers from 14 countries tested TMC114/ritonavir at 4 doses—400/100 mg and 800/100 mg once daily, and 400/100 mg and 600/100 mg twice daily—in 397 people with triple-class experience, 1 or more primary PI mutations, an average viral load of 4.61 log10 copies/mL, and an average CD4+ cell count of 136 cells/mm3. Baseline numbers were equivalent in a control group of 100 people randomized to start 1 or 2 alternative boosted PIs selected by their clinicians. Viral load declines at Week 24 averaged 1.85 logs with the highest dose of TMC114 vs 0.27 logs in the control arm in a noncompleter-equals-failure analysis (P < .0001). Mean viral load ebbs in the other TMC114 arms ranged from 1.34 to 1.47 logs. The highest-dose group gained an average 75 cells/mm3, compared with 15 cells/mm3 in the control group. Among people taking the highest dose of TMC114, 47% had a viral load under 50 copies/mL at Week 24 and 72% had at least a 10-fold drop in viral load. Of 40 people in the highest-dose group who had 3 or more primary protease mutations when they started the new PI, 19 had a viralload under 50 copies/mL 24 weeks later. Four of 397 people had to stop TMC114 because of side effects. Overall toxicity rates did not differ significantly between the combined TMC114 groups and the control group. Phase 3 studies using the 600/100-mg twice-daily dose of TMC114/ritonavir are slated to start later in 2005. [CROI 2005: http://clinicaloptions.com/hiv/news/news_CROI2005_11.asp] |
| TMC1252 | NNRTI | Possible activity against NNRTI-resistant HIV.
Single mutations which account for <2% of NNRTI mutations (Y181I, Y181V,
F227C and M230L) impose <10 fold increase in resistance in 4/59 isolates
tested. The non-nucleoside reverse
transcriptase inhibitor (NNRTI) TMC125 is safe, well-tolerated and effective
in HIV-positive patients with NNRTI and protease inhibitor resistance,
according to data from two studies presented last week at the Tenth European
AIDS Conference / European AIDS Clinical Society in Dublin. This indicates
that TMC125 could be the first NNRTI that can be used after the development
of resistance to other members of this drug class. Source: http://www.aidsmap.com/en/news/01fd2108-0bfd-41d3-93b0-7f5842d1ac79.asp |
| TMC126 | PI | Potent |
|
TMC120 (R147681) |
NNRTI | Potency similar to efavirenz |
| TMC278 | NNRTI | TMC278, an investigational
nonnucleoside reverse transcriptase inhibitor (NNRTI) reputed to have a high
barrier to resistance, passed a crucial step in clinical development—a 7-day
monotherapy test in treatment-naive patients.[1] The median viral
load drop measured 1.2 log10 copies/mL (more than 10-fold),
reported Frank Goebel, MD, from Munich's Ludwig Maximilians University, at
the 12th Conference on Retroviruses and Opportunistic Infections held in
Boston, Massachusetts. With activity against some NNRTI-resistant
virus,[2] TMC278 is the second of 2 NNRTIs under development at
Tibotec in Mechelen, Belgium. The drug's lengthy 38-hour half-life could
make once-daily dosing possible. Dr. Goebel and colleagues[1]
in Russia and Britain randomized 47 treatment-naive individuals to placebo
or 25 mg, 50 mg, 100 mg, or 150 mg TMC278 given once daily for 7 days as an
oral solution. Study participants began treatment with a median viral load
of 4.5 log10 copies/mL (range 3.5-5.9 log10 copies/mL)
and a median CD4+ cell count of 292 cells/mm3 (range, 29-590
cells/ mm3). After 7 days, the median HIV-1 load dropped
1.29 logs with TMC278 25 mg, 1.23 logs with 50 mg, 1.07 logs with 100 mg,
and 1.17 logs with 150 mg , there was no change with placebo (P value
vs placebo < .01 for all treatment groups). The apparent virologic
equivalence between arms prompted speculation at the conference that an even
lower dose may be possible. However, Dr. Goebel noted that longer treatment
may distinguish between the doses. No one stopped treatment because of
toxicity in this brief study, and no serious side effects were reported. The
median CD4+ cell count climbed 55 cells/mm3 in 7 days. A
multinational phase 2b dose-finding study begins in March 2005. [CROI 2005: http://clinicaloptions.com/hiv/news/news_CROI2005_9.asp] |
| T-1249 |
Fusion Inhibitor |
Not cross-resistant with enfuvirtide;
possible once-a-day subcutaneous dosing; injection site reactions possibly
less prominent (40%); rash and leukopenia are possible Development stopped January 2004 |
| SCH6 | HCV PI | May have significant activity against HCV |
| GW640385 | PI | Probably will be boosted with ritonavir; active against PI-resistant HIV? |
| RO033-4649 | PI | |
| TMC-1142 | PI | Likely will be boosted with ritonavir. May be active against many PI-resistant virus (1-3 primary PI mutations and resistance to up to 7 current PIs.) GI side effects. |
UK-427,857 |
CCR5 antagonist | Orally bioavailable; no activity against CXCR4+ HIV; expected launch 2008 |
| BMS-378806 |
gp120 binding blocker |
Produces a structural change in gp120; potentially active against CCR5 and CXCR4-binding viruses as well as subtype B HIV; orally bioavailable |
| BMS-4880431,2 | Attachment inhibitor | Oral compound with BID dosing which prevents the binding of the viral envelope protein gp120 to cellular CD4+ receptors. In a small study up to 1 log decrease in viral load was noted; however, the rate of viral decay was widely variable among the subjects. |
|
GSK-873,1401,2 aplaviroc |
CCR5 antagonist | Orally bioavailable. No
serious adverse effects noted. Administration with food increased
levels. Expected launch 2008?
Following 10 days of twice daily monotherapy, the largest viral load
reduction was seen in the 600 mg twice-daily group (mean decrease -1.6 log10
copies/mL). Reductions of -1.03, -1.23, -046 and -0.12 log10
copies/mL were seen in the 400 mg once-daily, 200 mg twice-daily, 200 mg
once-daily, and placebo groups, respectively.3 |
| PRO140 |
CCR5 blocker |
Human monoclonal antibody to CCR5 |
| GW8248 | NNRTI | Active against HIV with NNRTI-resistance mutations? |
| SPD-7542 | NRTI | Cytidine analog. Enantiomer of previously studied DOTC. May be active against NRTI-resistant strains of HIV. 1200 and 1600 mg/day dosing produced >1.5log reduction in viral load. No emergence of resistance mutations seen in one study. Lamivudine markedly reduces the intracellular phosphorylation of this compound. |
| SM-309515 | PI | JE-2147 class of transition-state mimetic dipeptide HIV PI molecules |
| PRO 5421 |
Attachment Inhibitor |
Expected launch 2008 |
|
SCH-D1,2 vicriviroc |
CCR5 antagonist | Oral CCR5 receptor antagonist.
Produces a 1-1.5 log viral load reductions at various dosages in a small
trial. One patient observed to have emergence of CXCR4 virus during
trial. Potential for drug interactions with other antiretrovirals. This compound was removed from study in treatment naive patients in October 2005 due to lack of efficacy as compared to a standard regimen. |
| TNX 3551,2 |
Anti-CD4 mAb |
A humanized anti-CD4 antibody, engineered by grafting murine proteins onto a human IgG4 antibody construct and then mutating amino acids in the framework to produce a structure that is 95% human. Various dosages produced about a 1 log decrease in viral load, but by week 9, viral load had returned to baseline and resistance to TNX 355 had developed. This may be the basis for designing similar therapies. |
|
Merck L-870,812 |
integrase inhibitor |
Under development for 10 years; prevents the last step of integration (strand transfer) |
|
Merck L-870,810 |
integrase inhibitor |
Sister drug to 812 above. In a trial, 30 HIV-positive patients were given placebo (6 patients) or 200 mg or 400 mg of L-870810 (7 and 17 patients, respectively). Fifteen of the 24 patients given the drug were antiretroviral (ARV)-experienced. After 10 days of twice-daily doses, the mean viral load decrease in the 200-mg and 400-mg doses was 1.73 and 1.77 log10 copies/mL, respectively (the latter is a 60-fold reduction in viral load). There was a wide range of response, from 0.95 to 2.49 log10 copies/mL, but no nonresponders. Six out of 16 patients on the higher dose (37.5%) had a viral load below 400 copies/mL by Day 10. After dosing was stopped, viral load increased again and was back to baseline by Day 24 in most subjects. This was the last study that will ever be performed on this specific compound. Research on L-870810 has now been stopped after unacceptable liver and kidney cell toxicity was found in dogs. One of the reasons for the slow progress on integrase inhibition is that many candidates have turned out to be toxic and to inhibit other vital cellular functions. However Little said that there was no evidence of human toxicity in the current study and that studies in rats had shown none. There were 4 discontinuations in this study; none were related to drug toxicity, and 3 were solely due to the suspension of the study when the dog toxicity data were released. Research on a related drug candidate L-870812 [above] is proceeding. [CROI 2005: http://clinicaloptions.com/hiv/news/news_CROI2005_16.asp] |
|
Shionogi-GSK S-1360 |
integrase inhibitor |
Extensive protein binding may be a
problem Development stopped early 20041 |
|
D-D4FC2 (Reverset) |
NRTI |
Cytidine analog. Half-life of 17 hours suggests once a day dosing possible. Q151, 69 insertion, and K65R produce resistance to this agent. 50 mg, 100 mg, and 200 mg/day each produced about 1.7log reduction in viral load. No significant adverse effects reported. |
|
Hepatitis B Therapy |
||
|
emtricitabine FTC |
NRTI | Cross-resistant with lamivudine; HBV resistance mutations selected in 19% after 2 years of therapy |
| entecavir | NRTI | Potent: 0.5 and 1.0 mg doses produce 2.8 and 2.5 log decreases in HBV DNA at 24 weeks and 3.8 and 4.4 log decreases at 48 weeks; 26% achieve undetectable levels at 48 weeks at both doses; best results with elevated transaminases at baseline; no significant adverse effects; effective against 3TC-resistance and in persons previously treated with interferon-alfa |
| telbivudine | NRTI | Additive or synergistic with lamivudine |
| clevudine | NRTI | |
| L-Fd4C | NRTI | |
|
amdoxovir DAPD |
NRTI | |
| famciclovir | anti-HSV | Less potent than lamivudine |
| thymosin | thymic-derived peptides | |
|
heteroaryldihydropyrimidines HAPs |
inhibit HBV nucleocapsid | |
As of mid 2005, there are
at least 83 antiretroviral therapies
for HIV under development.
If readers have information pertinent to any
antiviral investigational agents, please email me via the email address on the
homepage of this site.
| Click HERE for HIV Vaccination Information |
Last Updated 2/2/2013
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