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Current Opinion in HIV & AIDS:
doi: 10.1097/COH.0000000000000011
TREATMENT OPTIMISATION: Edited by David H. Brown Ripin, Charles W. Flexner and Ben Plumley

The antiretroviral drug pipeline: prospects and implications for future treatment research

Flexner, Charlesa; Saag, Michaelb

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aJohns Hopkins University School of Medicine and Bloomberg School of Public Health, Baltimore, Maryland

bUniversity of Alabama at Birmingham, Birmingham, Alabama, USA

Correspondence to Charles Flexner, MD, Johns Hopkins University School of Medicine and Bloomberg School of Public Health, Osler 527, 600 N. Wolfe Street, Baltimore, MD 21287-5554, USA. Tel: +1 410 955 9712; fax: +1 410 614 9978; e-mail: flex@jhmi.edu

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Abstract

Purpose of review: A number of investigational antiretroviral drugs in clinical development could alter the future treatment landscape for resource-limited settings and contribute to optimized therapy for HIV infection.

Recent findings: Several nucleoside reverse transcriptase inhibitors (NRTIs) are in development, including festinavir (BMS-986001), a thymidine analogue similar to stavudine but with reduced potential for toxicity, CMX-157, a hexadecyloxypropyl conjugate of tenofovir and tenofovir alafenamide (GS-7340), a prodrug of tenofovir achieving much higher intracellular triphosphate concentrations with a lower dose than tenofovir disoproxil fumarate. MK-1439 is a well tolerated once-daily non-NRTI (NNRTI) with activity against most NNRTI-associated resistance mutations. Albuvirtide is a long-acting parenteral fusion inhibitor related to enfuvirtide, and BMS-663068 is an oral HIV attachment/entry inhibitor. Ibalizumab (formerly TNX-355) is an mAb that binds to CD4 and lowers HIV plasma viral RNA in infected patients. Cenicriviroc is a CCR5-antagonist that also has activity against the inflammatory chemokine CCR2. The integrase strand transfer inhibitor (InSTI) dolutegravir was recently approved in the U.S. and is an attractive component of future regimens because of efficacy, tolerability, apparent safety and once-daily dosing; it also maintains some activity against raltegravir and elvitegravir-resistant mutants. The dolutegravir analogue GSK-1265744 appears to be equipotent and is being developed as a long-lasting injectable parenteral agent. The selective cytochrome P450 3A4 inhibitor cobicistat is a better tolerated alternative to ritonavir for pharmacokinetic ‘boosting’, but may also result in clinically undesirable drug interactions.

Summary: There are several investigational antiretroviral drugs with significant promise for inclusion in future primary and secondary combination regimens.

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INTRODUCTION

Chronic suppressive combination antiretroviral therapy has profoundly altered the course of the HIV epidemic and the lives of those infected with this virus. Despite the availability of 26 approved and marketed drugs, there is yet no ideal antiretroviral treatment combination, as defined by absolute efficacy, tolerability, convenience and safety. The target product profile for the ideal antiretroviral drug is summarized as follows:

1. Completely efficacious

2. Completely well tolerated

3. Convenient to use; user-friendly

4. Inexpensive; preferably available without charge to end-users

5. Universal, that is well tolerated and effective in all populations and under all circumstances of use

Powerful motives exist for the continued clinical development of new and better antiretroviral drugs. Classes of investigational antiretrovirals (ARVs) in clinical development include new nucleoside analogue reverse transcriptase inhibitors (nRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), integrase strand transfer inhibitors (InSTIs), entry inhibitors and fusion inhibitors. Many more agents with significant anti-HIV activity and favourable resistance profiles are in the preclinical stages of development and constitute a robust future clinical pipeline. This review will be confined to agents in current clinical development (see Fig. 1) [1].

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Choosing agents for clinical development should be guided by the success of the recent past. The current global standard of care for first-line treatment of adults, as recommended by the WHO, is a coformulated combination of efavirenz, lamivudine or emtricitabine, and tenofovir disoproxil fumarate (TDF) [2]. This regimen is highly effective and convenient for the patient to take, and is tolerant of occasionally missed doses because of the long half-lives of the parent or active metabolite of each of the component drugs [3▪▪]. The mean steady-state half-life is 40–55 h for efavirenz, 12–18 h for intracellular lamivudine triphosphate or 35–40 h for intracellular emtricitabine triphosphate, and 60–100 h for intracellular tenofovir diphosphate [4].

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Although this three-drug, one-pill, once-daily combination (marketed as Atripla in the USA) has radically altered the treatment landscape with its convenience, efficacy and persistence, the combination carries the possibility of some significant side effects. Efavirenz is associated with unacceptable central nervous system (CNS) toxicity in up to 10% of recipients, and tenofovir as the disoproxil fumarate is associated with long-term increases in serum creatinine and decreases in serum phosphate, with resulting concerns about nephrotoxicity and osteopenia, respectively.

An entirely nontoxic combination of antiretroviral drugs for first-line and second-line use would be an important advance for this field. Lamivudine, emtricitabine and raltegravir provide clinical proof-of-concept that long-term safety and minimal side effects are a possibility. New drugs in development can build on this concept in order to produce relatively nontoxic alternatives.

Special considerations for the next generation of antiretrovirals include the great diversity of HIV, and its common association with other infections. Although efavirenz and other NNRTIs are highly active against HIV-1, they lack activity against HIV-2 and cannot be used to treat that virus, which is common in West Africa [5]. Fortunately, NNRTIs are the only drug class with this vulnerability. Optimization of HIV treatment should focus on regimens also capable of controlling HIV-2, as their effectiveness would be more universal.

Hepatitis B virus (HBV) is one of the most common causes of chronic virus infection worldwide, and overlaps in geographic distribution with HIV. The nucleoside analogues lamivudine, emtricitabine and tenofovir are components of current first-line suppressive regimens for HBV infection and are desirable in regions with a high prevalence of concurrent infection [5]. Use of lamivudine or emtricitabine without tenofovir can lead to development of HBV resistance within 20 weeks of beginning therapy [6]. Discontinuation or switch of a regimen containing these nucleosides in a coinfected patient has been associated with rapid recurrence of HBV and acute liver disease.

Finally, although finding a low-cost drug is not generally a goal of pharmaceutical research and development in a profit-driven marketplace, future planning to ensure that a new drug has the greatest impact on the HIV epidemic should consider how that drug will be used in resource-poor settings. One strategy to lower costs once a drug becomes available as a generic is to minimize its mass dose [7▪▪]. Investigational drugs with lower daily mass doses are therefore more attractive for inclusion in optimized regimens.

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SPECIFIC DRUG CLASSES: NUCLEOSIDE ANALOGUE REVERSE TRANSCRIPTASE INHIBITORS

As the majority of treated patients continues to receive three-drug regimens containing two nRTIs, these drugs are likely to play an important role for the foreseeable future. Several investigational nRTIs are in advanced clinical development (see Fig. 1). Festinavir (BMS-986001) is a thymidine analogue structurally related to stavudine but with less potential for toxicity [8]. Festinavir is a more potent inhibitor of HIV replication than stavudine in vitro, but is 100-fold less potent in inhibiting the mitochondrial gamma-DNA polymerase. Festinavir also has less potential for stavudine-associated metabolic and renal toxicities, as indicated by its lack of effect on mitochondrial DNA in renal proximal tubular cells, muscle cells or adipocytes. The drug also does not alter cellular ATP levels or lactate production [8].

TDF, an oral prodrug of the nRTI tenofovir (TFV), remains the most widely prescribed antiretroviral drug worldwide. However, TDF use has been associated with Fanconi syndrome, and changes in estimated creatinine clearance and serum phosphate suggesting potential for causing long-term renal and bone toxicity. Several investigational prodrugs of TFV have been developed with better in-vitro potency against HIV and decreased potential for side effects.

TFV alafenamide (TAF; formerly GS-7340) is a more potent prodrug of tenofovir that produces substantially higher intracellular concentrations of the active TFV anabolite, tenofovir-diphosphate (TFV-DP), as a consequence of more efficient cellular uptake than seen with TDF [9▪]. Although intracellular concentrations of TFV-DP are higher, plasma concentrations of the parent drug are much lower than seen with TDF, possibly reducing the potential for renal or bone toxicity. In a 10-day monotherapy study compared with the standard 300 mg daily dose of TDF, median reduction in plasma HIV RNA concentrations was 0.76 log10 copies/ml with an 8 mg daily dose of TAF, 0.94 log10 copies/ml with a 25 mg daily dose and 1.08 log10 copies/ml with a 40 mg daily dose of TAF, as compared with 0.48 log10 copies/ml with 300 mg of TDF [9▪]. Although the plasma area under the concentration-time curve (AUC) for TFV was reduced by 79–96% with TAF, intracellular concentrations of TFV-DP were seven-fold higher with the 25 mg dose, and 20-fold higher with the 40 mg dose, than with TDF [9▪]. Thus far, TAF has not been associated with reductions in estimated creatinine clearance in patients and may have less potential for nephrotoxicity than TDF. An added advantage of TAF is the capacity for comparable reduction in viral load at a much lower daily mass dose than TDF, suggesting the possibility of lower cost as a generic equivalent.

CMX-157 is another investigational prodrug of TFV that is in Phase 2 clinical development. It is a lipid-based hexadecyloxypropyl prodrug of TFV that has in-vitro activity against all tested strains of HIV-1 and HIV-2 in human peripheral blood mononuclear cells (PBMCs) [10]. Exposure of cells to CMX-157 produced at least 30-fold higher intracellular concentrations of TFV-DP than TFV, presumably as a consequence of enhanced cellular uptake, similar to TAF. CMX-157 should inhibit intracellular HIV replication with lower plasma concentrations than achieved with a standard 300 mg daily dose of TDF, providing the potential for less long-term toxicity. Its in-vitro cytotoxicity profile is promising, but a recommended daily dose for treatment is not yet finalized. Whether it will have any clinical advantages over TAF remains to be determined. Both TAF and CMX-157 are expected to retain activity against HBV.

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NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

The NNRTI efavirenz is widely used as a component of first-line HIV treatment and has the advantages of high antiviral efficacy and a very long plasma half-life. Finding an NNRTI that shares the beneficial activity and pharmacokinetic profiles of efavirenz, but without the accompanying side effects, would represent a significant advance in HIV therapeutics.

MK-1439 (see Fig. 1) possesses many characteristics of the ideal target product profile, including high oral bioavailability, once-daily dosing, low potential for toxicity, compatibility in coformulation with other antiretroviral agents and activity against NNRTI-resistant HIV [11]. The drug-resistance pattern of MK-1439 is especially encouraging. Its 95% inhibitory concentration (IC95) against HIV-1 strains with the K103N mutation, conferring resistance to nevirapine and efavirenz, is 43 nmol/l, which is only two-fold higher than its IC95 against wild-type HIV. The IC95 against virus harbouring the Y181C mutation, conferring resistance to nevirapine, etravirine and rilpivirine, is 27 nmol/l. MK-1439 retains nearly full activity against viruses harbouring combinations of K103N, Y181C and G190A, which account for more than 90% of transmitted NNRTI resistance in the USA.

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ENTRY INHIBITORS

BMS-663068 is an investigational small molecule HIV attachment inhibitor. It is a methyl phosphate prodrug of BMS-626529, designed to improve the oral bioavailability of the active molecule. BMS-626529 binds directly to the viral envelope protein gp120, preventing the virus from binding to the CD4 receptor. This prevents virus from entering CD4+ target cells. In an 8-day monotherapy study [12], BMS-663068 caused HIV-1 plasma RNA to fall by 1–2 log10 copies/ml. However, there is a common polymorphism in the HIV-1 env gene conferring preexisting resistance to this drug in a minority of HIV strains; M426L is one such mutation. In patients harbouring susceptible virus strains, 8-day antiviral activity is much better, averaging 2–3 log10 copies/ml in monotherapy studies [13]. Future clinical development of BMS-663068 may require pretreatment screening for known resistance mutations before prescribing the drug, similar to strategies currently employed in the use of the CCR5 antagonist maraviroc.

Ibalizumab (formerly known as TNX-355) is a humanized mAb that selectively binds to the CD4 receptor in a manner that prevents HIV entry into CD4+ target cells [14]. The antibody has activity against both CCR5- and CXCR4-tropic viruses. In a Phase lB multidose study, 19 HIV-infected patients received either 10 mg/kg of intravenous ibalizumab weekly or a 10 mg/kg loading dose followed by 6 mg/kg every 2 weeks for 9 weeks. Three patients received 25 mg/kg every 2 weeks for five doses. Despite the fact that these patients were receiving no other antiretrovirals, or were maintained on a stable failing regimen, ibalizumab lowered HIV-1 plasma RNA by 0.5–1.7 log10 copies/ml in most individuals [14]. Curiously, HIV-1 plasma viral load returned to baseline after 1–2 weeks in most individuals despite continued treatment. Apparent resistance to ibalizumab emerged in vitro in most of these individuals, although the molecular mechanism appears to be complex, as ibalizumab-resistant isolates remained CD4 dependent [14].

More effort will be needed to define the reasons for ibalizumab treatment failure, and how well the drug performs in combination with effective oral antiretrovirals. Although this drug is likely to be too expensive for use in resource-limited settings, its availability is important for the development of parenteral antiretroviral combinations for those who would benefit from such regimens [15]. In the future, ibalizumab and related anti-HIV mAbs could be used in long-acting injectable combination regimens for HIV treatment and/or prevention; this topic is covered elsewhere in this issue of Current Opinion (Spreen et al., pp. 565–571).

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FUSION INHIBITORS

Only one HIV fusion inhibitor, enfuvirtide, is still available, and it is a costly injectable drug given twice daily (b.i.d.).

Albuvirtide is an enfuvirtide analogue that is a 3-maleimimidopropionic acid-modified injectable peptide [16]. Similar to enfuvirtide, albuvirtide binds to the transmembrane portion of the HIV envelope glycoprotein gp41, and prevents membrane fusion. Because this drug can conjugate to serum albumin, it has a much longer plasma half-life than enfuvirtide, reportedly as long as 11 days [16]. As a consequence, albuvirtide could be given as infrequently as once a week, or perhaps less frequently. Initial studies reported a one log10 reduction in plasma HIV RNA with a single 320 mg intravenous dose. Injection site reactions were observed at higher doses in phase I studies, as was the case with enfuvirtide [16].

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CCR5 ANTAGONISTS

One CCR5 antagonist, maraviroc, is approved for first-line and second-line HIV treatment and is being studied as an agent for preexposure prophylaxis (PreP). A second CCR5 antagonist, vicriviroc, had significant anti-HIV activity in Phase 2 studies, but its development was terminated after disappointing activity in treatment-experienced individuals in Phase 3 [17]. There are no antagonists of the CXCR4 chemokine receptor in clinical development for HIV at present.

Cenicriviroc (CVC) is an investigational oral antagonist of CCR5 that also has inhibitory activity against the CCR2 chemokine receptor [18]. CVC blocks HIV use of the CCR5 chemokine coreceptor and thus prevents virus entry into host cells. CVC also blocks the binding of CCR5 ligands RANTES and macrophage inflammatory protein (MIP-1) to CCR5, and of monocyte chemotactic protein-1 (MCP-1) to CCR2 [18]. This finding suggests that CVC has significant potential for anti-inflammatory effects in patients, unlike maraviroc, and could have a role in treating the chronic immune activation associated with suppressed HIV infection, in addition to its direct anti-HIV effects.

In a randomized, double-blinded Phase 2B trial in treatment-naìve individuals, 24 weeks of CVC along with emtricitabine (FTC) and tenofovir (TDF) produced an undetectable HIV plasma viral load (<50 copies/ml) in 76% of those taking CVC 100 mg, 73% of those taking CVC 200 mg daily and 71% of those taking a standard EFV/FTC/TDF control regimen [19]. Only one out of 113 CVC recipients discontinued treatment due to AEs, compared with five out of 28 EFV recipients. This indicates that CVC has short-term efficacy comparable to EFV when combined with NRTIs in treatment-naive patients, and may be better tolerated. CVC produced a dose-dependent increase in MCP-1, the native ligand for CCR2, and a decrease in sCD14, a monocytes activation biomarker, as compared with EFV [19]. An added potential advantage of CVC is its lower daily mass dose [100 or 200 mg daily (q.d.)] than maraviroc. CVC will share with maraviroc the drawback of requiring phenotypic or genotypic testing for chemokine receptor usage prior to prescription, and is expected to have no activity against CXCR4-tropic virus.

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INTEGRASE STRAND TRANSFER INHIBITORS

Two InSTIs are approved for treatment in the U.S. Raltegravir is a highly effective and well tolerated drug, but must be given twice daily. Elvitegravir is a once-daily drug, but must be given in combination with a pharmacokinetic enhancer, the selective cytochrome P450 3A4 inhibitor cobicistat (see below).

Dolutegravir was granted regulatory approval in the USA on August 12, 2013, and has the potential advantages of once-daily dosing without the need for pharmacokinetic enhancement with an enzyme inhibitor. An additional potentially useful feature of this drug is a low daily mass dose of 50 mg. Dolutegravir retains antiviral activity in patients who have failed raltegravir or who harbour raltegravir or elvitegravir resistance mutations [20▪].

In the SPRING-1 phase 2B study, dolutegravir at doses of 10, 25 or 50 mg q.d. along with NRTIs produced better virologic response rates in treatment-naive patients than the control arm of efavirenz-based therapy. No InSTI-associated resistance mutations were observed in the dolutegravir groups through 96 weeks of treatment. Treatment discontinuation due to adverse events occurred in 3% of dolutegravir-treated patients compared with 10% on the efavirenz arms [20▪]. In a noninferiority trial comparing dolutegravir 50 mg once-daily as well as abacavir/lamivudine (n = 414) with efavirenz/emtricitabine/tenofovir (n = 419) in treatment-naive patients, the dolutegravir regimen produced a statistically significantly higher response rate than the efavirenz regimen at 48 weeks (viral load less than 50 copies/ml in 88 vs. 81% of patients) [21]. The median time to response was statistically significantly shorter in the dolutegravir group than in the efavirenz group (28 vs. 84 days, P < 0.0001). The mean increase in CD4+ cell count was also statistically significantly greater with dolutegravir than with efavirenz (267 vs. 208 cells/μl; P < 0.001). The efavirenz/emtricitabine/tenofovir combination was associated with higher rates of discontinuation due to adverse events (10 vs. 2% with dolutegravir) and a higher incidence of liver function abnormalities (9 vs. 2%, respectively) than dolutegravir [21].

The dolutegravir dose for treatment-naive patients is expected to be 50 mg once daily, with 50 mg b.i.d. used for patients who have failed raltegravir or elvitegravir. In a Phase 2 study in patients with raltegravir resistance, the primary endpoint of HIV RNA less than 400 copies/ml or a minimum –0.7 log10 copies/ml was achieved in 78% of 27 patients receiving 50 mg dolutegravir once daily and 96% of 24 patients receiving 50 mg dolutegravir b.i.d. [22]. A plasma viral load of less than 400 copies/ml was achieved in 41% of the once-daily group and in 54% of the b.i.d. group [22].

Virologic failure with dolutegravir has not been accompanied by emergence of resistance mutations in treatment-naive patients, in contrast to the resistance seen with raltegravir and elvitegravir. Dolutegravir treatment has been associated with a small increase in serum creatinine, due to inhibition of proximal tubule enzyme systems similar to what is seen with cobicistat; this has persisted for 48 weeks and results in a 0.1–0.15 mg/dl increase in serum creatinine without affecting actual glomerular filtration rate (GFR) [23]. Dolutegravir may be given in combination with rifampin if its dose is doubled to 50 mg b.i.d., or given with rifabutin without dose modification [24]. This may allow the use of dolutegravir in combination with drugs to treat tuberculosis, and provides an alternative to efavirenz-containing regimens in this setting.

A dolutegravir analogue, GSK-1265744, is also in Phase 2 clinical development as an oral agent for treatment (see Fig. 1). However, the greatest interest in this agent is in its use as a long-lasting parenteral antiretroviral, as it is chemically more compatible with nanosuspension technology than dolutegravir. Given as a single intramuscular injection of 400 mg, nanoformulated GSK-1265744 produces measurable plasma concentrations in healthy volunteers for up to 48 weeks. This formulation is under investigation in prevention strategies given every 3 months, or in treatment strategies given as a monthly injection. GSK-1265744 and related compounds are covered in more depth elsewhere in this issue of Current Opinion (Spreen et al., pp. 565–571).

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COBICISTAT AS A PHARMACOKINETIC ENHANCER

Although not an actual antiretroviral drug, cobicistat is being investigated as an alternative to ritonavir for ‘boosting’ the pharmacokinetic profile of coadministered antiretrovirals, especially HIV protease inhibitors. Cobicistat was recently approved by the United States Food and Drug Administration (FDA) as part of a once-daily, single-tablet coformulation with elvitegravir, tenofovir and emtricitabine. In a prospective randomized trial comparing cobicistat-boosted atazanavir with ritonavir-boosted atazanavir (atazanavir/r), virologic suppression was equivalent at 48 weeks in the two arms (85% in the cobicistat group, n = 344; 87% in the ritonavir group, n = 348) [25]. Adverse events leading to treatment discontinuation and overall adverse events were also similar in the two groups.

Interest in cobicistat relates mainly to its potential for less toxicity than ritonavir, especially gastrointestinal side effects and hyperlipidemia [26▪]. In a pooled analysis of Phase 3 studies, elvitegravir/cobicistat/emtricitabine/tenofovir was associated with smaller increases in total cholesterol levels (10 vs. 19 mg/dl; P < 0.001) and low-density lipoprotein (LDL) cholesterol (10 vs. 17 mg/dl; P < 0.001) than efavirenz/emtricitabine/tenofovir, and a smaller increase in triglycerides (8 vs. 23 mg/dl; P = 0.006) than atazanavir/r plus tenofovir/emtricitabine [27].

It is important to note that cobicistat produces an increase in serum creatinine via inhibition of secretion of creatinine through proximal renal tubules. Because this increase is not associated with an actual reduction in glomerular filtration rate (true creatinine clearance), this results in a reduction in estimated GFR without changing actual GFR by direct measurement, similar to a phenomenon seen with other approved drugs such as trimethoprim [26▪]. As a consequence, serum creatinine may increase by a mean of 0.1–0.15 mg/dl during the first 2–4 weeks of treatment. In the atazanavir/cobicistat vs. atazanavir/r trial, there was an early increase in serum creatinine and a reduction in estimated GFR in the cobicistat group compared with the ritonavir group, with the differences remaining statistically significant at week 48 (median increase in serum creatinine 0.13 vs. 0.09 mg/dl; P < 0.001; median decrease in estimated GFR –13 vs. –9 ml/min; P < 0.001) [25].

Another advantage of cobicistat over ritonavir is its lack of inherent antiviral activity. This negates any potential for cobicistat to promote the emergence of HIV protease inhibitor resistance if it is used in regimens lacking an active HIV protease inhibitor such as atazanavir. This could also make cobicistat a preferred pharmacokinetic enhancer for use in non-HIV related applications, for example as a pharmacokinetic booster for hepatitis C virus (HCV) protease inhibitors. Cobicistat is equipotent as ritonavir in inhibiting cytochrome P450 3A4 at its approved dose of 150 mg per day, although it is not known to be a P450 inducer. It thus retains a similar potential for undesirable drug–drug interactions involving CYP 3A4 inhibition as ritonavir.

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CONCLUSION

The need for new antiretroviral agents that meet the ideal target product profile remains great. Aside from obvious goals of long-term safety and persistence, optimized HIV therapy calls for regimens that cover both HIV-1 and HIV-2 and can therefore be used universally. Coverage of hepatitis B virus is also desirable, given the high prevalence of this infection in places where HIV is now endemic. Compatibility of antiretroviral drugs with agents used to treat concurrent disease such as tuberculosis is important. New drugs in the clinical pipeline will provide more and better choices for optimized regimen development, and increase confidence that more people in more diverse settings will derive the full benefits of antiretroviral treatment.

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Acknowledgements

None.

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Conflicts of interest

C.F. reports receiving grant support from GlaxoSmithKline for research unrelated to this manuscript; has served as a consultant to Bristol-Myers Squibb, Boehringer-Ingelheim, Gilead Sciences, GlaxoSmithKline, Merck, Roche/Genentech, Tobira Therapeutics and ViiV. M.S. has received grants and research support from and/or has been a scientific advisor to Ardea Biosciences, Inc, Avexa Ltd, Boehringer Ingelheim Pharmaceuticals, Inc, Bristol-Myers Squibb, Gilead Sciences, Inc, GlaxoSmithKline, Merck & Co, Inc, Pfizer Inc, Tibotec Therapeutics, Vertex Pharmaceuticals, Inc, and ViiV Healthcare.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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REFERENCES

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This published trial emphasizes the long-term safety, tolerability and efficacy of the new InSTI dolutegravir.

21. Walmsley S, Antela A, Clumeck N, et al.Dolutegravir (DTG; S/GSK1349572) + abacavir/lamivudine once daily statistically superior to tenofovir/emtricitabine/efavirenz: 48-week results – SINGLE (ING114467). 52nd Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), 9–12 September 2012; San Francisco, CA; 2014 [Abstract H-556b].

22. Cahn P, Pozniak AL, Mingrone H, et al. on behalf of the extended SAILING Study TeamDolutegravir versus raltegravir in antiretroviral-experienced, integrase-inhibitor-naive adults with HIV: week 48 results from the randomised, double-blind, noninferiority SAILING study. Lancet 2013; 382:700–708.

23. Koteff J, Borland J, Chen S, et al. A phase 1 study to evaluate the effect of dolutegravir on renal function via measurement of iohexol and para-aminohippurate clearance in healthy subjects. Br J Clin Pharmacol 2013; 75:990–996.

24. Dooley KE, Sayre P, Borland J, et al. Safety, tolerability, and pharmacokinetics of the HIV integrase inhibitor dolutegravir given twice daily with rifampin or once daily with rifabutin: results of a phase 1 study among healthy subjects. J Acquir Immune Defic Syndr 2013; 62:21–27.

25. Gallant JE, Koenig E, Andrade-Villanueva J, et al. Cobicistat versus ritonavir as a pharmacoenhancer of atazanavir plus emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV type 1-infected patients: week 48 results. J Infect Dis 2013; 208:32–39.

26▪. German P, Liu HC, Szwarcberg J, et al. Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function. J Acquir Immune Defic Syndr 2012; 61:32–40.

This careful study examines the mechanism by which drugs such as cobicistat can increase serum creatinine and cause modest reductions in estimated GFR without affecting actual GFR.

27. Ward D, Crofoot G, Shamblaw D, et al.Efficacy and safety of elvitegravir/cobicistat/emtricitabine/tenofovir DF from an integrated analysis of phase 2 and 3 clinical trials. 52nd Interscience Conference on Antimicrobials and Chemotherapy (ICAAC), 9–12 September 2012; San Francisco, CA; 2014 [Abstract H-555].

Keywords:

antiretroviral therapy; CCR5 antagonist; entry inhibitor; fusion inhibitor; integrase strand transfer inhibitor; nonnucleoside reverse transcriptase inhibitor; nucleoside reverse transcriptase inhibitor

© 2013 Lippincott Williams & Wilkins, Inc.

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