Antiretroviral pipeline 2010

Simon Collins


Current HIV drugs are sufficiently safe, potent, and effective for recent modeling studies to suggest that, for someone newly infected with HIV, life expectancy should be approaching that of an HIV-negative person. [1, 2]

This is dependent on access to care and treatment, and such models usually exclude complications such as hepatitis C or tuberculosis coinfection or ongoing drug use. Therefore, any review of pipeline drugs must acknowledge that these assumptions for normalizing life expectancy currently apply to a minority of patients globally unless universal access and uptake can be achieved.

At levels of viral suppression to <50 copies/mL, HIV evolution is not slowed, but stopped, [3] with the evidence suggesting that residual virus is more likely to originate from latently infected resting cells than from ongoing replication in a part of the body not reached by treatment. [4] Treatment is more effective than people realise. Recent studies using more sensitive viral load tests suggest that perhaps more than 50% of people suppressed to <50 copies/mL generally have HIV RNA <5 copies/mL. [5, 6] At these low levels, further intensification has no additional impact on viral load in plasma or in sanctuary sites such as the central nervous system. [7, 8] New drugs and classes need to be designed to increase flexibility to adherence with the potential for new delivery methods and smaller molecular weight formulations to reduce costs. So the bar for new drugs is set higher, but this, by definition, has always been the case.

Virological failure rates are low. In some settings, rates of viral failure in people on stable suppression therapy are less than 5% annually, [9] supported by pharmacokinetic profiles that allow the maintenance of therapeutic levels of some drugs after the strict dosing time. [10]

However, rates for switching HIV treatment due to toxicity or tolerability are significantly higher, showing that tolerability is still clinically significant. Other examples of unmet antiretroviral (ARV) need include combinations that:

  • treat people with multidrug resistance;
  • protect against or reverse central fat accumulation;
  • do not increase the risk of metabolic complications (lipids, glucose, bone);
  • increase CD4 counts for the approximately 10% of people who respond virologically but not immunologically.

New therapies active against mutidrug-resistant (MDR) HIV are needed and will be lifesaving. The absolute number of people each year who become unable to construct a combination that includes at least two active drugs is currently low, estimated at perhaps 1,500 people annually in the United States. This means that a growing number of people now have resistance to five classes of ARVs. Globally, resistance to only three classes may reduce or eliminate further treatment options because of the more limited formulary in many developing countries.

For these MDR patients to benefit from treatment advances, flexibility in and new approaches to trial design are required. For example, trials need to allow people who do not have the required number of active drugs for an optimized background regimen in phase III studies to be able to use more than one unlicensed compound in a research setting. [11] The risk:benefit ratio for an MDR treatment is different from one developed for treatment-naive patients. The broadest indication for any ARV is a more lucrative market. However, using orphan-drug designation for MDR HIV might generate sufficient financial incentives to develop lifesaving drugs for this special population. Antiviral efficacy has far greater priority for an MDR treatment than do formulation, adherence, or convenience of dosing.

This is an area where renewed activist focus on treatments for experienced patients is needed.

Many of the newer drugs and classes are not yet widely available in developing countries, where barriers to market entry include, at the highest level, lack of World Health Organization (WHO) inclusion on the essential medicines list or in the 2009 WHO ARV guidelines, and at the country level lack of registration, regulatory capacity, high prices, and lack of clarity on how best to use these newer agents.

Treatments in developed countries are much safer and more protective than was previously assumed. [12] If people are to start treatment earlier, the need exists for them to become safer still. The limitations of current ARV use include late diagnosis, unequal access to treatment, and complications related to social stigma including drug and alcohol use and discrimination based on gender and sexual orientation.

Within the last year, ARV treatment has achieved a more deserved and central position in prevention, as potentially among the most effective biomedical prevention strategies (see the chapter on Immune-Based Therapies and Preventive Technologies Pipeline). However, the ideals of universal access to treatment, and widespread use of treatment at high CD4 cell counts, is in stark contrast to the current reality in which the median CD4 count for patients in developed countries upon diagnosis remains <250 copies/mm3 and is significantly lower in most resource-poor settings. [13]

Finally, any discussion of ARVs in the context of earlier treatment involves the question of when to start therapy. This raises the importance of accurate data on both the benefits and the risks of treatment in order to define a CD4 threshold for when to start, acknowledging that absolute CD4 counts are imperfect surrogate markers. This is currently the focus of the National Institute of Allergy and Infectious Diseases–funded START study that will randomise 4,000 patients with a CD4 count >500 copies/mm3 to either immediate HIV treatment or to defer initiation until the CD4 count reaches 350 cells/mm3.

Notably, large randomised studies also provide the opportunity to study the pathology of HIV disease and its interaction with treatment, other illnesses, and age-related morbidity. With ARV treatment options unlikely to change radically in the next few years, this is a stable and opportune time for such research. [14]

We need new drugs. The antiretroviral pipeline in 2010 that is detailed below, focusing predominantly on compounds in phase II or phase III development or with in vivo data on virologic activity, looks surprisingly strong. Many of these compounds will be active against MDR HIV. However, the development of some compounds with potential activity has been suspended due, at least in part, to financial reluctance from investors.

The global demand for alternatives to lifelong treatment, compounded by economics that are beginning to cap treatment programs both in the United States and internationally, is discussed more fully in the introduction to this report and has reinvigorated the urgency for strategies focused on a cure (see the chapter on Immune-Based Therapies and Preventive Technologies Pipeline).

Activity since 2008

There are no guarantees in drug development, even for compounds that complete phase III studies. Predicting pipeline development is a similar process. It is therefore perhaps most significant that none of the ARVs that were listed as pipeline compounds in TAG’s 2008 Pipeline Report have been approved as new treatment. The only new ARV to be approved by the U.S. Food and Drug Administration (FDA) since 2008 for sale in the United States has been a Meltrex formulation of the protease inhibitor ritonavir in January 2010. The principal advance this has is heat stability, no longer requiring refrigerated storage. However, the time taken for this development attracted criticism for Abbott, the drug’s producer, since it came five years after the same compound had been coformulated with lopinavir in a heat-stable version of Kaletra. [15]

Of seven compounds listed in 2008, only two (rilpivirine and elvitegravir) continue in phase III studies; one (TNX-355) has remained in tentative phase II and four (vicriviroc, bevirimat, apricitabine and amdoxovir) have been put on hold or discontinued (see Table 1).

Table 1: The status of pipeline compounds from the tag 2008 report

Compound Class Status Comment
Rilpivirine NNRTI Phase III Submission 3Q 2010
Elvitegravir Integrase Phase III Phase III complete 2011/12
Ibalizumab (TNX-355) CD4 mAb Phase IIb Phase IIb CD4-specific monoclonal antibody (mAb)
Vicriviroc CCR5 Discontinued (Ph 3) On hold; efficacy vs. placebo
Bevirimat Maturation Phase IIb Development suspended
Apricitabine * RTI Discontinued (phase 2) No financial backing for phase III studies
Amdoxovir RTI Discontinued (phase 2) No recent data published on ongoing studies

Notes: NNRTI = nonnucleoside reverse transcriptase inhibitor; mAb = monoclonal antibody; RTI = reverse transcriptase inhibitor.

* Although financial backing is still sought, in July 2010 Avexa reinstated their commitment to develop apricitabine. [58]

In the unfortunately named Victor-E phase III studies, the CCR5-inhibitor vicriviroc, when added to optimized background therapy, failed to show benefit compared to placebo in treatment-experienced patients. While the issue of the strength of background therapy has been discussed, darunavir and/or raltegravir were only used by 25–40% of people and etravirine was not available. Approximately 65% of the participants had >3 active drugs (defined by baseline genotypic sensitivity) and only 30–40% of the participants had two or fewer active drugs. At least some of the differences in antiviral activity of vicriviroc compared to placebo were likely to be obscured by an uneven distribution of baseline resistance in the active compared to control arms. This difference was not sufficiently promising for Merck, which acquired vicriviroc when the company bought Schering Plough in 2009, to continue development in experienced patients. [16] Although treatment-naive studies continued for a few months, in July 2010, these were also discontinued. [17]

Bevirimat (now MPC-4326 with Myriad, and formerly PA-457 with Panacos) is a maturation inhibitor that has had a long development history dating back to a ten-day monotherapy activity study back in 2005. [18] While further efficacy data have not been presented, a phase IIb dose-finding study in treatment-experienced patients was started in November 2009. [19] The drug has reduced activity in around one-third of treatment-naive patients with HIV subtype B due to naturally occurring polymorphisms in the Gag cleavage site and greater levels were expected with subtype C. In protease-resistant patients the proportion of non-responders was estimated at 45%. [20] Disappointingly, in June 2010, Myriad announced in a press release that development was now suspended, stating financial pressure and a decision to focus on oncology. [21] This can only have been hastened by commentary three months earlier in the journal AIDS suggesting “future development should be abandoned.” [22] From an activist perspective this is alarming because conversely the molecule potentially retained activity for 55% of people with multiple drug resistance.

Apricitabine (AVX754, formerly Shire SPD754), a cytidine analogue similar to 3TC, with activity against M184V resistance, with or without additional thymidine or other nucleoside analogue mutations (either TAM pathway, L74V etc), and no further development of mutations following 21 days monotherapy. In the phase 2 AVX-201 study apricitabine, showed viral load reductions of –0.7 log for people with three or more TAMS, [23] but has since failed to move into phase III. The Australian biotech company Avexa announced the end of the development program in a press release in May 2010, explaining its inability to find an investment partner to back further development on the limited market for twice-daily medication. [24] This is another missed opportunity for MDR options. [Note: The decision to discontinue the development programme was reversed as a shareholders meeting citing community support for the need for effective treatments for people with multidrug resistance.] [59]

Finally, the development of amdoxovir (DAPD), a purine nucleoside analogue with activity against M184V and other reverse transcriptase inhibitor–associated mutations, has maintained a low profile, perhaps because its potential to reduce resistance to AZT when used in the same combination currently has reduced applicability now that AZT is less commonly recommended in Western countries. The last presentation on the development of this compound was at the Conference of Retroviruses and Opportunistic Infections (CROI) 2008, published this year, that reported -2.0 log reduction in viral load after 10 days of 500 mg amdoxovir plus 200 mg AZT, showing synergistic activity compared to monotherapy. [25, 26]  Until 2004, amdoxovir was in development by Gilead, under license from Emory University and the University of Georgia Research Foundation, who acquired the compound when they bought Triangle Pharmaceutical in 2003.

The positive news is that both rilpivirine and elvitegravir are proceeding in phase III studies, while TNX-355 (ibalizumab, now TMB-355 with TaiMed) currently has ongoing studies but they are moving slowly.

The ARV pipeline in 2010

Fortunately, newer compounds expand the 2010 pipeline (see table 2),  which does not include new formulations of existing drugs such as the extended-release nevirapine that may be submitted later this year or the once-daily formulation or indication for raltegravir.

Of the compounds in phase III development, rilpivirine (formally TMC-278) is likely to be submitted to the FDA this year, and potentially an additional fixed-dose combination (FDC) of rilpivirine/tenofovir/FTC.

Rilpivirine is a nonnucleoside reverse transcriptase inhibitor (NNRTI) from Tibotec that showed short-term activity of –1.2 log in the phase 2a monotherapy study. [27] This year top-line results from two phase III studies in treatment-naive patients (TMC278-C209 and C215) have already been reported. When used in combination with tenofovir/FTC, rilpivirine is reported to be noninferior compared to efavirenz, based on the primary endpoint of viral suppression, <50 copies/mL at week 48. Results are due to be presented at the Eighteenth International AIDS Conference in Vienna in July 2010. These will determine submission to the FDA, which is anticipated in the summer of 2010. [28]

Results for rilpivirine from phase II studies at 96 weeks reported lower rates of side effects including reduced rash, lower central nervous system toxicity, less sleep disturbance, and fewer lipid changes compared to efavirenz. However, grade 3 and 4 side effects and laboratory abnormalities were similar, so while these results are encouraging this is a compound that suggests an improved rather than clean tolerability profile. Early concerns about cardiovascular toxicity (from prolonged QTc intervals, although stabilized), were largely overcome by selection of the 25mg dose. [29]  If there is wide interpatient variability in drug levels, the low dose would need to demonstrate the proportion of patients failing to achieve the minimum effective concentration (MEC). Efficacy compared to Atripla (the combination efavirenz/tenofovir/FTC) are also likely to determine uptake and use. With intent-to-treat analysis both efficacy and tolerability contribute to primary analysis and both should be tracked closely when phase III results are presented. The once-daily low-dose (25mg) formulation supports easier development in FDCs, including the Gilead-led formulation with tenofovir/FTC mentioned above. [30]  If current bioequivalence studies are successful, this could see regulatory submission for FDCs before the end of 2010. Additionally, a slow-delivery formulation requiring an injection every four weeks is currently undergoing pharmacokinetic studies, potentially for both postexposure prophylaxis and treatment indications. NOTE: the bioequivalence study was presented at the IAS Conference in Vienna. [59]

The next most promising pipeline compounds are from Gilead, singly or in fixed-dose formulations: an integrase inhibitor (elvitegravir), a pharmacokinetic booster (cobicistat, previously GS 9350), and the Quad FDC that combines both with tenofovir/FTC. While the four-in-one FDC is the clearly preferred lead, development issues could see earlier submission to regulatory agencies of a coformulated elvitegravir plus cobicistat or even stand-alone cobicistat. Submission for these compounds is unlikely before 2012. Limited data are available on these compounds.

When Quad (n=48) was compared to Atripla (n=23) in the 236-0104 phase II study, 90% vs 83% (NS: weighted difference +5% 95%CI –11.0% to +21.1%) of patients had an undetectable viral load (<50 copies/mL) at 24 weeks by intent-to-treat, missing=failure analysis (ITT M=F). [31]  Patients were treatment-naive, with no documented resistance and were HBV/HCV negative. Mean age was 35, approximately 90% of participants were Caucasian, baseline CD4 was 389 vs 450 in the Quad vs Atripla groups and 4–6% had an AIDS diagnosis. However, mean baseline viral load was low at <40,000 copies/mL (4.6 log), and only 25% of people had levels >100,000 copies/mL. Patients in the Quad group (n = 48) became undetectable more quickly than those on Atripla (n = 23) which is likely to be an integrase class effect, as this was also seen with raltegravir, though it has not shown clinical significance so far. After eight weeks, about 80% of people had undetectable viral loads with Quad, compared to about 50% with Atripla. Quad was better tolerated in terms of lack of efavirenz-related side effects (35% vs 57% with any grade 1–4 drug-related adverse event). This was driven by reduced CNS toxicity: abnormal dreams 10% vs. 35%; dizziness 0 vs. 13%; fatigue 8 vs 13%; somnolence 4 vs. 9%). There were three discontinuations in each arm, with one due to adverse events (in the Atripla group). A caution was also reported due to the impact of cobicistat on reducing estimated—but not actual—glomerular filtration rate suggests that a new management algorithm for renal toxicity will need to be developed.

Results from a second phase II study (216-0105), this time comparing the new booster cobicistat (n = 50) to ritonavir (n = 29) in the same population, each in combination with atazanavir plus tenofovir/FTC, showed limited differences in efficacy or tolerability between the two boosters. Virological responses were 84% vs 86% (ITT M=F; NS: weighted difference –1.9% 95%CI –18.4 to +14.7) in the cobicistat vs. ritonavir groups respectively.  Grade 1–4 adverse events occurred in 20 vs 24% with grade 3/4 events in 4% vs. 0 patients. GI tolerability was similar (diarrhea 6% vs 10% but nausea 10% vs. 3%). Similar small median increases were seen in cholesterol, HDL, LDL and triglycerides in each arm but grade 2–4 increases in total cholesterol were higher in with cobicistat (6% vs 0) and in amylase (12% vs. 7%). These are tiny numbers but while data are too limited for a detailed comparison, cobicistat appears to have similar GI, lipid, and cytokine P450 3A4-boosting activity to ritonavir, which is not ideal. Unlike ritonavir, cobicistat has no antiretroviral activity. [32]

These small studies are promising. Quad, elvitegravir, and cobicistat are all currently in larger phase III studies and nothing should be assumed until we see the results. Quad is also going head-to-head against Atripla (mainly in the United States) and against atazanavir/ritonavir plus tenofovir/FTC in the United States, Europe, South America, and Asia. [33, 34] Cobicistat is going head-to-head against ritonavir with atazanavir plus tenofovir/FTC. [35]

While cobicistat may not yet have demonstrated advantages over ritonavir on tolerability and toxicity, it may have the advantage of allowing easier and potentially cheaper coformulated FDCs. If this compound is safe and effective, Gilead will be spared royalty payments to Abbott, and the example with Atripla may be an indication that collaborations could follow with other companies whose drugs require boosting.

In 2008, Sequoia, Tibotec, and Pfizer had booster compounds in early development, but none of these have reported further progress in vivo. Phase I study results of the Sequoia compound SPI-452 in HIV-negative individuals showed proof-of-concept boosting activity with atazanavir or darunavir; these were presented at CROI 2009. [36]

The booster from Tibotec (TMC558445) completed single and multiple escalation phase I studies to increase darunavir or Tibotec’s investigational protease inhibitor TMC310911 in HIV-negative volunteers. [37] For results to have neither been presented nor published indicates that both TMC558445 and TMC310911 are unlikely to advance along the pipeline, at least in the short term. [38]

The pharmacokinetic booster PF-03716539 was one of the compounds coming from Pfizer when it formed a joint venture with GlaxoSmithKline (GSK) in 2009 to form ViiV Healthcare. Although a phase I study in HIV-negative people was completed, the results have not been published or presented, nor other studies listed. The ViiV pipeline is probably led by the integrase inhibitor GSK1349572, developed by GSK in partnership with Shionogi. Phase IIb dose-ranging results are expected to be presented at the Eighteenth International AIDS conference in Vienna, [39] and Phase IIb studies in integrase-experienced patients are already ongoing. [40] A broad range of drug-to-drug interaction studies, mostly already completed, [41] indicate confidence in GSK1349572, and phase III studies are likely to start enrollment before the end of the year. This compound is a once-daily formulation that does not require pharmacokinetic boosting and has potential for coformulation with abcavir/3TC.

ViiV also has two NNRTI compounds. GSK2248761 is the development name (formerly IDX-12899) for the compound bought by GSK from Idenix. Antiviral activity was shown in results from a seven-day Phase I/IIa dose-finding study in Argentina in 40 treatment-naive patients randomised 8:2 to once-daily monotherapy with 800mg, 400mg, 200mg or placebo. All patients switched to 28 days monotherapy or started HAART at the end of the study period.  Results were available for all but two patients in each of the 200mg and placebo arms. Viral activity was similar in each of the active drug groups, which saw steady, linear viral load reductions reaching -1.8 log at day eight from mean baseline of approximately 4.3-4.6 log copies/mL [42] Though further efficacy data have not been presented, a phase IIb dose ranging study is due to start later in 2010. ViiV also acquired UK-453061 (lersivirine) from the joint venture with Pfizer, with even more distant efficacy results (from 2007, but published in 2009). In 48 treatment naive patients, mean viral load reductions at day 8 of 0.3, 0.8, 1.3 and 1.6 log after receiving 10, 30, 100 and 500 mg twice daily, respectively, and 0.9, 1.7 and 1.8 log after receiving 100, 500 and 750 mg once daily, respectively. [43, 44] However, the lersivirine phase IIb studies in naive patients compared against efavirenz are ongoing and may report results in early 2011. Drug interaction and/or formulation studies are ongoing in HIV-negative groups. As both compounds showed similar approximate reductions in viral load of at least –1.7 logs following 7-days monotherapy one of these compounds will be prioritised for development, with dual-stage development for the same class unlikely.

As a result of a collaboration with Concert Pharmaceuticals announced last year, [45] GSK is developing a deuterium-based protease inhibitor (CTP-518) that is similar to atazanavir but may not need pharmacokinetic boosting; this is still in preclinical development.

At the end of 2008, interesting results from an NNRTI developed by Ardea Bio (RDEA806) showed viral load reductions of 1.5–2.0 log following seven days of monotherapy in 12 treatment-naive patients. [46] It is disappointing that nothing further has been heard about this compound, with this most likely due to failure to find a development partner.

Other compounds in phase IIb studies include two entry inhibitors (an attachment inhibitor from Bristol-Myers Squibb (BMS) about which little is known, and a CCR5 inhibitor from Tobira), a long-term development survivor (a monoclonal antibody ibalizumab–which has been listed in every TAG Pipeline Report at least since 2004), and a tenofovir-like nucleoside reverse transcriptase inhibitor (from Chimerix). BMS is currently enrolling HIV-positive patients in a phase II dose-finding study of an attachment inhibitor called BMS-663068, with and without ritonavir, at a single site in Berlin. However, few details have been published from earlier studies or on its mechanism of action. [47]

A dose-finding phase I study of the CCR5 inhibitor (with off-target CCR2activity) called TBR-652 from Tobira was presented at CROI 2010. [48] These first results in 54 HIV-positive patients produced median viral load reductions of 1.7 log with the 50mg, 75mg, and 150mg doses after ten days of monotherapy. Although baseline viral load was lower in the 150mg group (median 4.0 logs, compared to 4.5 and 4.6 logs in the 50mg and 75mg groups), all patients using the 75mg dose had >1.0 log reductions. Patients were treatment-experienced (though off treatment for at least six weeks), CCR5-naive and CCR5-positive. No dose-related or serious side effects were reported. Mild side effects (none reported at the 75mg dose) included nausea, diarrhea, headache, and fatigue in greater frequency at the 100 and 150mg doses, although many of these were reported as being in a single patient with a concomitant infection. The compound has a plasma half-life of 35–40 hours, allowing once-daily dosing and although metabolised by CYP and non-CYP pathways is neither an inducer nor inhibitor of CYP P450. [NOTE: Phase II results were presented in July 2010]. [60]

The monoclonal antibody ibalizumab in development with TaiMed Biologics since 2007 (now TMB-355, formerly TNX-355 with Tanox) has had a similarly long development history, and is still listed as having a phase II dose-finding study in treatment-experienced patients. Ibalizumab is given by intravenous infusion every two to four weeks. [49, 50] Although there are interesting plans to include ibalizumab in studies with other investigational drugs in people with multiclass resistance, it is unclear whether this will be delayed by a decision to focus on a new formulation.

Finally, in the reverse transcriptase inhibitor class, CMX-157, a prodrug of tenofovir, which has activity against broad RTI-associated resistance at lower dose concentrations, [51] has just entered phase I studies with Chimerix in HIV-negative volunteers. [52] A financial backer for this compound will be needed for the development timeline to quicken, as Chimerix is a small biotech with no other antiretrovirals in development.

Table 2. Pipeline compounds in 2010 with demonstrated activity in humans

Compound Company Class Status Comment
Rilpivirine Tibotec NNRTI Phase III FDA submission expected 3Q10.
Rilpivirine/ tenofovir/FTC Tibotec FDC (NNRTI + RTIs) Pharmacokinetic equivalence FDA submission based on equivalence studies is possible before the end of 2010
Elvitegravir Gilead Integrase inhibitor Phase III Phase III expected to complete by 2011–12.
Cobicistat Gilead Pharmacokinetic enhancer Phase III P450 CYP 3A4 inhibitor/ protease inhibitor booster.
Elvitegravir/cobici- stat/tenofovir/FTC (Quad) Gilead FDC (boosted integrase +RTIs Phase III Phase III expected to complete by 2011–12.
GSK1349572 ViiV/ Shionogi Integrase inhibitor Phase IIb Ongoing study in patients with raltegravir resistance. Results expected in July 2010.
GSK2248761 (IDX-12899) ViiV NNRTI Phase II Second-generation NNRTI, currently in pharmacokinetic studies. Activity showed potency in phase I monotherapy study.
UK-453061 (lersivirine) ViiV NNRTI Phase II (lersivirine) Viral load reductions of -1.8 log following ten-day monotherapy.
CTP-518 GSK Protease inhibitor Phase I Deuterium-based protease inhibitor.
RDEA806 Ardea Bio NNRTI Phase IIa Viral load reductions of 1.5–2.0 log, but failure to find development partner.
BMS-663068 BMS Attachment inhibitor Phase II Dose-ranging study +/- ritonavir is ongoing.
bevirimat (MPC-4326; was PA-457) Myriad Maturation inhibitor Phase IIb Treatment for experienced patients.  Resistance testing required for screening
ibalizumab (TMB-355, was TNX-355) TaiMed Biologics CD4 mAb Phase IIb (TMB-355, was TNX-355) Biologics  Ibalizumab; CD4-specific humanized IgG4 monoclonal antibody administered by intravenous infusion every two weeks or four weeks.
TBR-652 CCR5 (also active against CCR2) Phase I Median -1.7 log reductions after ten-day monotherapy with 75mg, 100mg, and 150mg doses.
CMX-157 NRTI Phase I RTI similar to tenofovir, currently in pharmacokinetic studies. Activity showed potency in phase I monotherapy study.
SPI-251 Pharmacokinetic enhancer Phase II P450 CYP 3A4 inhibitor/protease inhibitor booster. Boosting data in vivo but no HIV-positive data.
PF-3716539 Pharmacokinetic enhancer Phase I ViiV P450 CYP 3A4 inhibitor/protease inhibitor booster.
TMC558445 Tibotec Pharmacokinetic enhancer Phase I P450 CYP 3A4 inhibitor/protease inhibitor booster. Development on hold.
TMC-310911 Tibotec Protease inhibitor Phase I Development on hold.

Other compounds and targets in preclinical research

New approaches to HIV treatment, mainly in preclinical preliminary studies, include non-antiretroviral targets and approaches, including attempts to target latently infected cells.

Some of these were presented at CROI 2010 included a new class of integrase inhibitor called LEDGINS, unlikely to be cross-resistant to raltegravir or elvitegravir, as they do not bind at the active site. These potential molecules, 2-(quinolin-3-yl) acetic acid derivatives, were designed by rational drug design and identified after screening 200,000 molecules. Two early compounds that could interfere with the assembly and stability of the capsid core are in development at Boehringer Ingleheim. [54]

Now, at least five new types of treatment are the focus of research on how to target latently infected cells. These include cellular restriction factors—human proteins that reduce HIV replication and that can help or block infection—such as tetherin, a protein that blocks HIV release; APOBEC3, an immunity gene that has anti-HIV activity; and TRIM5-alpha, a protein that in some monkeys protects against HIV infection. Gene therapy could perhaps be modified to adapt the related human protein.

A compound in development with Koronis (KP-1461) that had shown interesting results in vitro as a viral decay accelerator failed to show significant activity in vivo in a phase IIa study. Although the mechanism of increasing the error replication rate to a point when the virus becomes unable to sustain further replication is intriguing, this would not impact latently infected cells and, even if successful, implies limited clinical application.

Another new approach in phase I for both treatment-naive and -experienced patients, including immunological nonresponders, is the compound SB-728 (in development by Sangamo) that is using zinc finger nuclease–modified CD4 cells delivered by infusion to inhibit CCR-5 binding. [55]

Patent expiry and generic compounds

The next few years will see additional patents expire for many of the earlier ARVs. The ARV pipeline could technically include in Western countries generic FDCs that were prevented by previous patent restrictions.

However, production and approval of generic AZT and ddI did not lead to either the availability of new drugs that were significantly cheaper nor to any widespread shift in prescription policy, even when some savings could occur. This is reassuring given the poorer tolerability of these earlier RTIs.

In 2009, 3TC and abacavir (both from GSK in 2009, now ViiV) came off patent,56 with the next in line being saquinavir (Invirase; Roche worldwide) in November 2010, nevirapine (Viramune; Boehringer Ingelheim) in 2011, and combination AZT/3TC (Combivir; ViiV) in 2012.

The balance of safety, efficacy, and certainly convenience remains with more recently approved drugs and more contemporary FDCs, but many of these soon-to-be-available generic options, while not included as preferred choices in treatment guidelines, are still used by at least 10–20% of people.

It is unclear why larger cost reductions have not followed patent expiry, but this may change in the future. Health care systems in Western countries are coming under increasing pressure to include cost as a factor, and the potential for limited treatment choices for poorer patients is a concern that HIV activists will need to counter with an awareness of the data showing the clinical limitations of these choices.

Conversely, generic companies may bring coformulated FDCs to Western countries that have long been available outside the United States.

Over the last year, some companies have left the HIV research field and others have entered it. Several of the largest companies pursued mergers: Roche, although announcing in 2008 that it had ceased HIV research, announced a take over of Genentech for $47 billion earlier last year, and the company is still active in hepatitis C virus (HCV) therapeutics. GSK created a joint venture with Pfizer to launch the new HIV-specific development company called ViiV (with GSK holding an 85% share and Pfizer 15%, subject to changes in market share), and Merck acquired Schering Plough in a $41 billion merger in November 2009. ViiV is marketing both GSK and Pfizer’s legacy antiretrovirals and developing new ones, while Merck is integrating Schering’s HCV and HIV pipelines into its own (with some trimming as appropriate).

Many research companies are investing in generic manufacturing plants in countries where production costs are likely to be lower, blurring the concerns about generic versus brand formulations, as long as each individual drug manufacturing facility has undergone regulatory approval.


This review should demonstrate reasons for optimism in the ARV pipeline. The effectiveness of current treatment ensures, in the absence of a cure, that HIV-positive people are a growing population and therefore remain a lucrative market for investment. It is worrying when the development of potential treatments are suspended or discontinued and a lack of financial backing is cited as the cause. But drug development is a commercial activity and, like much in industry—pharmaceutical or otherwise—details are obscured when it comes to costs and development plans. The public health aspect of medicine has yet to impact on a wider knowledge of these costs. The necessity to maintain stock prices may drive company press announcements more than accurate details about the activity (or lack thereof) of pipeline compounds. The information in this report is susceptible to these influences, just as trial results only tell a limited story.

The demand for new and better drugs remains high for each stage of treatment management, and the protective impact of antiretrovirals in suppressing viral load and, in turn, reducing infections should drive the need for new drugs as powerfully as it should drive the demand for broader access to care and treatment. In 2010, after more than 25 years of research into treatment and prevention, these two fields are more neatly joined than more people imagined or wanted. The benefits of earlier treatment are plausibly supported by many studies highlighting the potential negative implications of unsuppressed viremia. The shift to treating at higher CD4 counts raises the importance of really long-term tolerability. Treatment needs to be used for up to 40 years for adults, and much longer for children.

The ARV pipeline for resource-limited countries led the world in the availability of fixed-dose generic combinations that were never available in Western countries, but the timeline for access to the latest drugs remains imperiled due to patent restrictions.

The newest pipeline drugs have seen both patient and financial benefits overlap for promising combinations, and this looks set to continue in the immediate future, within and among Western companies.

However, the greatest clinical need—patients with broad class resistance—currently provides a lower financial incentive compared to an ARV approved with a treatment-naive indication. This shows the need for activist pressure for new regulatory solutions. Fortunately, drugs developed for one group often have the potential to be as effective in the other, but when this isn’t the case—and oftpounds with lifesaving potential.


Unless stated otherwise, all web links were retrieved on 29 June 2010.

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  3. Tobin NL et al. Evidence that low-level viremias during effective HAART result from two processes: Expression of archival virus and replication of virus. J Virology, August 2005 (79) 9625–34.
  4. Dinoso JB et al. Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. PNAS online, 22 May 2009, doi: 10.1073/pnas.0903107106.
  5. Gianotti N et al. Predictors of attaining <1 plasma HIV/RNA copies/ml in a large Italian cross-sectional study. (Poster abstract 499.) Paper presented at the Seventeenth Conference of Retroviruses and Opportunistic Infections 2010, San Francisco, 16–19 February 2010.
  6. Gandhi R et al. Raltegravir (RAL) intensification does not reduce low-level residual viremia in HIV-1-infected patients on antiretroviral therapy (ART): Results from ACTG A5244. (Late breaker oral abstract WELBB104.) Paper presented at the Fifth IAS Conference on HIV Pathogenesis, Treatment, and Prevention, Cape Town, South Africa, 19–22 July 2009.
  7. Ghandi et al. Ibid.
  8. Maldarelli F et al. Intensification with efavirenz or lopinavir/r does not reduce residual HIV-viraemia in patients on standardised ARV therapy. (Abstract 72.2.) Paper presented at the Seventeenth International HIV Drug Resistance Workshop, 6–10 June 2008, Sitges, Spain.
  9. Benzie AA et al. Increased duration of viral suppression is associated with lower viral rebound rates in patients with previous treatment failures. AIDS 2007;21(11):1423–30. t/2007/07110/Increased_duration_of_viral_suppression_is.5.aspx
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  11. Struble K et al. Antiretroviral therapies for treatment-experienced patients: Current status and research challenges. AIDS 2005;19(8):747–56. /Fulltext/2005/05200/Antiretroviral_therapies_for_treatment_experienced.1.aspx.
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  13. Althoff K et al. Late Presentation for HIV Care in the US and Canada. (Poster abstract 982.) Paper presented at the Seventeenth Conference of Retroviruses and Opportunistic Infections 2010, San Francisco, 16–19 February 2010.
  14. U.S. National Institutes of Health. Strategic Timing of Antiretroviral Treatment (START).
  15. Medecins Sans Frontiers, Campaign for Access to Essential Medicines. Approval of heat-stable ritonavir ends years of neglect by Abbott: Years of medical double standards and stranglehold by Abbott come to an end” (12 February 2010).
  16. Gathe J et al. Phase 3 trials of vicriviroc in treatment-experienced subjects demonstrate safety but not significantly superior efficacy over potent background regimens alone. (Oral abstract 54LB.) Paper presented at the Seventeenth Conference of Retroviruses and Opportunistic Infections 2010, San Francisco, 16–19 February 2010.
  17. Merck Vicriviroc Discontinued Investigator Letter (9 July 2010). Retrieved 12 August 2010.
  18. Beatty G et al. Safety and antiviral activity of PA-457, the first-in-class maturation inhibitor, in a 10-day monotherapy study in HIV-1 infected patients. (Abstract H-416d.) Paper presented at the Forty-fifth Interscience Conference on Antimicrobial Agents and Chemotherapy, 16–19 December 2005, Washington, DC.
  19. U.S. National Institutes of Health. A study to assess the long-term efficacy (24 weeks) of MPC-4326 in combination with a 2–3 drug OBR relative to the efficacy of a 3–4 drug ARV regimen in treatment experienced HIV-1 infected subjects who are failing current antiretroviral therapy.
  20. Verheyen J et al. High prevalence of bevirimat resistance mutations in protease inhibitor–resistant HIV isolates. AIDS 2010;24:5. 669–673.
  21. Myriad Pharmaceuticals. Myriad Pharmaceuticals announces intent to focus on oncology portfolio (8 June 2010).
  22. Wainberg MA, Albert J. Can the further clinical development of bevirimat be justified? AIDS 2010; 24(5): 773–74. /Fulltext/2010/03130/Can_the_further_clinical_development_of_bevirimat.18.aspx.
  23. Cahn P et al. 48-week data from Study AVX-201—A randomised phase IIb study of apricitabine in treatment-experienced patients with M184V and NRTI resistance. (Abstract O414.) Paper presented at the Ninth International Congress on Drug Therapy in HIV Infection, 9–13 November 2008, Glasgow, Scotland.
  24. Avexa. Avexa closes apricitabine (ATC) program (10 May 2010).
  25. Murphy R et al. Pharmacokinetics and potent anti-HIV-1 activity of amdoxovir plus zidovudine in a randomised double-blind placebo-controlled study. (Poster abstract 794.) Paper presented at the Fifteenth Conference on Retroviruses and Opportunistic Infections, Boston, 3–6 February 2008.
  26. Murphy R et al. Antiviral activity and tolerability of amdoxovir with zidovudine in a randomised double-blind placebo-controlled study in HIV-1-infected individuals. Antivir Ther. 2010;15(2):185–92.
  27. Goebel F et al. Short-term antiviral activity of TMC278—a novel NNRTI—in treatment-naive HIV-1-infected subjects. AIDS: 22 August 2006. Volume 20 Issue 13 – p 1721-1726] Fulltext/2006/08220/Short_term_antiviral_activity_of_TMC278___a_novel.5.aspx.
  28. Gilead Sciences. Gilead provides update on development of fixed-dose regimen of Truvada and Tibotec Pharmaceuticals’ TMC278 (20 April 2010).
  29. Santoscoy M et al. TMC278 (rilpivirine), a next-generation NNRTI, demonstrates long-term efficacy and tolerability in ARV-naive patients: 96-week results of study C204. (Oral abstract TUAB0103.) Paper presented at the Seventeenth International AIDS Conference, 3–8 August 2008, Mexico City.
  30. GileadSciences. Gilead provides update on development of fixed-dose regimen of Truvada and Tibotec Pharmaceuticals’ TMC278 (20 April 2010).
  31. Cohen C et al. Single-tablet, fixed-dose regimen of elvitegravir/emtricitabine/tenofovir disoproxil fumarate/GS-9350 achieves a high rate of virologic suppression and GS-9350 is an effective booster. (Oral abstract 58LB.) Paper presented at the Seventeenth Conference of Retroviruses and Opportunistic Infections 2010, San Francisco, 16–19 February 2010.
  32. Cohen C et al. ibid.
  33. U.S. National Institutes of Health. Study to evaluate the safety and efficacy of elvitegravir/emtricitabine/tenofovir disoproxil fumarate/GS-9350 versus ritonavir-boosted atazanavir plus emtricitabine/tenofovir disoproxil fumarate in HIV-1 infected, antiretroviral treatment-naive adults.
  34. U.S. National Institutes of Health. Phase 3, randomised, double-blind study to evaluate the safety and efficacy of elvitegravir/emtricitabine/tenofovir disoproxil fumarate/GS-9350 versus efavirenz/emtricitabine/tenofovir disoproxil fumarate in HIV-1 infected, antiretroviral treatment-naive adults.
  35. U.S. National Institutes of Health. Phase 3, randomised, double-blind study to evaluate the safety and efficacy of GS-9350-boosted atazanavir versus ritonavir-boosted atazanavir each administered with emtricitabine/tenofovir disoproxil fumarate in HIV-1 infected, antiretroviral treatment-naive adults.
  36. Gulnik S et al. Preclinical and early clinical evaluation of SPI-452, a new pharmacokinetic enhancer. (Oral abstract 41). Paper presented at the Sixteenth Conference on Retroviruses and Opportunistic Infections, Montreal, 8–11 February 2009.
  37. U.S. National Institutes of Health. PEPI-TiDP23-C103: First-in-human study to examine the safety, tolerability, and plasma pharmacokinetics of increasing single and repeated oral doses of TMC558445 and of a combined single day dosing of oral TMC558445 and oral TMC310911 and also oral darunavir.
  38. U.S. National Institutes of Health. A study to evaluate the safety, tolerability and pharmacokinetics of single oral doses of PF-03716539 in healthy adult subjects.
  39. U.S. National Institutes of Health. A dose ranging trial of GSK1349572 and 2 NRTI in HIV-1 infected, therapy naive subjects (ING112276).
  40. U.S. National Institutes of Health. A clinical research study for assessing the effectiveness of the new integrase inhibitor GSK1349572 in HIV-infected persons with prior antiretroviral treatment and resistance to raltegravir.
  41. U.S. National Institutes of Health. List of GSK1349572 studies.
  42. Zala C et al. IDX899, a novel HIV-1 NNRTI with high barrier to resistance, provides suppression of HIV viral load in treatment-naive HIV-1-infected subjects. (Abstract THAB0402). Paper presented at the Seventeenth International AIDS Conference, Mexico City, 3–8 August 2008.
  43. Fatkenheuer G et al. Short-term monotherapy with UK-453,061, a novel NNRTI, reduces viral load in HIV-infected patients. (Abstract WESS202.) Paper presented at the Fourth IAS Conference on HIV Pathogenesis, Treatment and Prevention, 22–25 July 2007, Sydney, Australia.
  44. Fatkenheuer G et al. Activity, pharmacokinetics and safety of lersivirine (UK-453,061), a next-generation nonnucleoside reverse transcriptase inhibitor, during 7-day monotherapy in HIV-1-infected patients. AIDS 2009;23(16):2115–22.
  45. GlaxoSmithKline. GSK and Concert Pharmaceuticals form alliance to develop novel deuterium-modified drugs (2 June 2009). .
  46. Moyle G et al. RDEA806, a novel HIV NNTRI, shows positive outcome in treatment of naive HIV patients. (Abstract H-893.) Paper presented at the Forty-eighth Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, 25–28 October 2008, Washington DC.
  47. U.S. National Institutes of Health. Pharmacodynamics, safety and pharmacokinetics of BMS-663068, an HIV attachment inhibitor, in HIV-1.
  48. Palleja S et al. Safety and efficacy of TBR 652, a CCR5 antagonist, in HIV-1-infected, ART-experienced, CCR5 antagonist-naive patients. (Oral abstract 53.) Paper presented at the Seventeenth Conference of Retroviruses and Opportunistic Infections 2010, San Francisco, 16–19 February 2010.
  49. U.S. National Institutes of Health. Dose-response study of ibalizumab (monoclonal antibody) plus optimized background regimen in patients with HIV-1 (TMB-202).
  50. Jacobson J et al. Safety, pharmacokinetics, and antiretroviral activity of multiple doses of ibalizumab (formerly TNX-355), an anti-CD4 monoclonal antibody, in human immunodeficiency virus type 1–infected adults. Antimicrobial Agents and Chemotherapy 2009;53(2):450-457; doi:10.1128/AAC.00942-08.
  51. Lanier ER et al. Hexadecyloxpropyl tenofovir (CMX157) has enhanced potency in vitro against NRTI resistant HIV relative to tenofovir and a favorable preclinical profile. (Poster Abstract 4.) Paper presented at the Seventeenth International HIV Drug Resistance Workshop, 6–10 June 2008, Sitges, Spain.
  52. Chimerix. Chimerix initiates Phase 1 Study CMX157, (13 May 2010). http://www.chimerix-inc .com/news-and-resources/news-and-resources-details/10-05-13-chimerix-initiates-phase-1-study-cmx157/.
  53. Christ F et al. First-in-class inhibitors of LEDGF/p75–integrase interaction and HIV replication. (Oral abstract 49.) Paper presented at the Seventeenth Conference of Retroviruses and Opportunistic Infections 2010, San Francisco, 16–19 February 2010.
  54. Titolo S et al. Discovery of potent HIV-1 capsid assembly inhibitors. (Oral abstract 50.) Paper presented at the Seventeenth Conference of Retroviruses and Opportunistic Infections 2010, San Francisco, 16–19 February 2010.
  55. U.S. National Institutes of Health. Autologous T-cells genetically modified at the CCR5 gene by zinc finger nucleases SB-728 for HIV (zinc-finger). amp;recr=Open&rank=226.
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  57. U.S. Food and Drug Administration. Orange book:Approved drug products with therapeutic equivalence evaluations.
  58. Avexa Press Release: Quarterly News Report to Shareholders for July 2010. (23 July 2010). Retrieved online 12 August 2010. News Report to Shareholders for July 2010.pdf.
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  60. Martin DE et al. TBR-652, a potent dual chemokine receptor 5/chemokine receptor 2 (CCR5/CCR2) antagonist in phase 2 development for treatment of HIV infection. (Abstract MOAB0104). Paper presented at the Eighteenth International AIDS Conference, Vienna, 18–23 July 2010. Retrieved online 12 August 2010.

Links to other websites are current at date of posting but not maintained.