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5 Newer Classes: Entry Inhibitors and Integrase Inhibitors

5 Newer Classes: Entry Inhibitors and Integrase Inhibitors

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4.5 Newer Classes: Entry Inhibitors and Integrase Inhibitors


HIV Entry Mechanism

2. Co-receptor









3a. Anchorage


1. CD4




R5 or X4




3c. Fusion






HIV 3b. coil-coil


Figure 4.6 Mechanism of action of the HIV entry inhibitors.

tropism assay optimized their background regimens on the basis of treatment history

and drug-resistance testing, and then were randomized to receive either maraviroc

(at one of two doses) or matching placebo [57]. In total, 46% of the maraviroc twicedaily recipients compared to 17% of placebo recipients had HIV RNA <50 copies

mlÀ1 at week 48 (p < 0.001). Since maraviroc was the first antiretroviral drug to target

a host immune cell receptor, concerns about immune effects or unusual toxicities

have been raised. In patients congenitally lacking the CCR5 receptor, there are

demonstrable immune effects, e.g. increased morbidity and mortality following West

Nile Virus infection [58]. However, no excess hepatic toxicity, unusual infections or

malignancies were associated with maraviroc use in the MOTIVATE studies, in

contrast to other investigational CCR5 antagonists [59, 60]. Of note, the Food and

Drug Administration (FDA) required that all study subjects who received a CCR5

antagonist in a clinical trial be followed for clinical events for five years. The use of

CCR5 antagonists in developing countries represents a major challenge due to a need

for the viral tropism assay. The concomitant treatment of TB and HIV with a

maraviroc-containing regimen is also complicated by a significant drug–drug

interaction, whereby rifampin cause a >60% decrease in maraviroc concentrations

that would necessitate the maraviroc dose to be adjusted. At present, no data are

available regarding any interactions of maraviroc with rifabutin [20].


Integrase Inhibitors

The most recently approved member of a new class of drugs was the strand transfer

integrase inhibitor, raltegravir. The HIV integrase enzyme catalyzes three steps of

j 4 HIV/AIDS Drugs


Viral DNA Synthesis




of 3'Ends




Assembly on Viral DNA in a

Nucleoprotein Complex


Nuclear Me








Target DNA


and joining

Gap Repall

Strand Transfer




Figure 4.7 Mechanism of action of the HIV integrase inhibitors.

integration: (1) formation of the double-stranded viral DNA complex; (2) the 30 processing of the DNA; and (3) transport and insertion of the viral DNA into the host

cell DNA in a process called “strand transfer” [61] (Figure 4.7). Raltegravir was

approved in 2007 on the basis of demonstrating significant virologic activity in the

benchmark studies of 699 treatment-experienced patients in the BENCHMRK

studies, whereby 62% of raltegravir versus 33% of placebo recipients had HIV RNA

<50 copies mlÀ1 at 48 weeks (p < 0.001) [62]. However, the majority of patients who

experienced virologic failure also developed drug resistance to raltegravir [63].

Raltegravir also was compared to efavirenz, both in combination with NRTIs, in a

Phase II study of treatment-na€ıve patients and demonstrated comparable virologic

suppression rates with 85–95% of patients having HIV RNA <50 copies mlÀ1

through 48 weeks [64, 65]. Raltegravir demonstrated a side-effect profile similar to

that of placebo in all of these studies. Whilst raltegravir is metabolized by glucuronidation, concomitant administration with rifampin causes a 40–60% decrease in

raltegravir concentrations, thus complicating the concomitant treatment of TB [20].

In summary, drugs with new mechanisms of action, such as HIV entry inhibitors

and integrase inhibitors, have demonstrated significant virologic activity in patients

with resistance to NRTIs, NNRTIs, and PIs. Consequently, new drugs have revolutionized the goals and management of treatment-experienced patients, setting a new

standard of virologic response: HIV RNA levels suppressed to <50 copies mlÀ1 [20,

21]. Unfortunately, these newer drugs are limited by their higher cost, the need for

parenteral administration of enfuvirtide the restriction of activity to R5 virus (only)

and the need for the tropism assay, in the case of maraviroc, and a low barrier to

resistance for raltegravir. Significant drug–drug interactions of maraviroc or raltegravir with rifampin also further complicate the use of these drugs.

4.6 Newer Strategies


Newer Strategies

While current combination antiretroviral therapy regimens are highly effective, their

limitations of convenience, tolerability, toxicity, drug–drug interactions and activity

against drug-resistant viral strains continue to prompt the search for new strategies

and newer antiretroviral agents. The current preferred initial therapy for HIV

infection is a regimen consisting of two NRTIs in combination with an NNRTI or

a ritonavir-boosted PI [20, 21] (Table 4.3), on the basis of results from large

randomized, comparative clinical trials [7, 14, 30, 41, 45, 47]. Studies comparing

preferred NNRTI-based regimens with PI regimens have demonstrated distinct

benefits to both strategies [42, 44], and support either approach.

Newer strategies for treatment-na€ıve patients include some novel approaches. AllNRTI regimens have the potential to avoid drug–drug interactions, particularly with

the hepatically metabolized NNRTIs and PIs and TB drugs. However, three-NRTI

regimens are less potent than NNRTI-based regimens [22], while four-NRTI regimens have not yet been studied extensively [23] and could have toxicity problems of

their own. An NRTI-sparing approach to avoid NRTI-related toxicities also has been

explored, typically consisting of an NNRTI together with a ritonavir-boosted PI.

However, these regimens have been associated with toxicity [30] and/or increased

rates of drug resistance at virologic failure [42], continue to have significant

drug–drug interaction issues, and have not been adopted widely.

Newer compounds may challenge the existing drugs and treatment paradigms

(Table 4.4). When combined with dual NRTIs, an investigational NNRTI – rilpivirine –

showed comparable virologic responses to efavirenz but was associated with fewer

rashes and central nervous system toxicity in a Phase II study for up to 96 weeks [66].

Rilpivirine is currently under investigation in large Phase III studies. Rilpivirine is

also available in an investigational nanoparticle formulation with a prolonged drug

Table 4.4 Investigational antiretroviral agents in clinical development (partial list only).

Stage of



Phase III

Phase II

Phase I/II




dexelvucitabine UK-453,061




Phase I










PRO 140









PRO 542

PPL-100 PF-232798


SPI-256 SCH-532706

TBR 652



j 4 HIV/AIDS Drugs


half-life that allows dosing as infrequently as once a month [67]. Additional newer

formulations of antiretroviral agents may allow infrequent dosing of antiretroviral


Newer drugs approved for treatment-experienced patients also may offer benefits

to treatment-na€ıve patients as part of combination regimens. For example, darunavir

was non-inferior virologically to lopinavir/ritonavir and had fewer side effects [52].

Maraviroc was non-inferior to efavirenz as part of a three-drug regimen for the HIV

RNA <400 copies mlÀ1 endpoint, but not for <50 copies mlÀ1 [68], although tropism

assay sensitivity most likely played a role. A raltegravir-based regimen had comparable virologic responses to an efavirenz-based regimen over 96 weeks, and a

statistically significantly more rapid time to virologic suppression [64, 69]; similarly

designed Phase III raltegravir studies provided similar preliminary results [65].

With the development of these newer agents in treatment-na€ıve patients, new

potentially paradigm-shifting strategies could be tested that could spare several

classes of drugs. For example, the combination of a PI with an integrase inhibitor or a

CCR5 antagonist could spare both NRTIs and NNRTIs. Similarly, a standard

combination regimen of NRTIs and an NNRTI could be used first and then, after

regimen failure, a new regimen consisting of a PI with an integrase inhibitor or a

CCR5 antagonist could be used. This would define a sequence of two fully potent

antiretroviral therapy regimens with distinct mechanisms of action and nonoverlapping drug resistance profiles, although drug–drug interactions (including those

with TB medications) would complicate these new approaches. Consequently, pilot

studies investigating such possibilities are currently in progress.

For patients with significant treatment experience, the current guidelines recommend reviewing the treatment history, performing drug-resistance testing, and

designing a regimen with two (or preferably three) fully active agents in the next

regimen [20, 21]. A number of investigational compounds in existing classes

(NRTIs, NNRTIs, PIs), in newer approved classes (CCR5 antagonists, integrase

inhibitors), or in investigational classes (CD4 attachment inhibitors, CXCR4

antagonists, maturation inhibitors) have demonstrated activity against drugresistant viruses, and may be particularly useful for treatment-experienced patients

if they are proved safe and effective (Table 4.4). Today, the “pipeline” for new

antiretroviral agents appears full.


Concomitant Treatment of HIV Infection and Tuberculosis

The current guidelines emphasize that the treatment of HIV-infected patients with

active TB should follow the same principles as for HIV-infected patients without

TB [20]. Although the optimum time to start antiretroviral therapy in patients with

active TB is not known, a number of clinical trials are under way [70]. Neither are

the optimal antiretroviral regimens to treat HIV-infected patients with TB known,

although NRTI combinations that do not cause peripheral neuropathy (e.g.,

abacavir/lamivudine, tenofovir/emtricitabine, or zidovudine/lamivudine), in


combination with a NNRTI with manageable drug interactions and a lower potential

for overlapping hepatotoxicity (e.g., efavirenz), have demonstrated virologic outcomes that are not different from those in treated HIV-infected patients without

TB [29]. The treatment of HIV and TB can be successfully managed, and the

integration of care and treatment for both infections is clearly critical. In addition,

clinical trials are in progress that will continue to define the optimal strategies for

concomitant treatment [70].



The development of effective antiretroviral therapy changed the natural history of

HIV disease, with dramatic decreases in morbidity and mortality worldwide. Today,

the life expectancy of HIV-infected people receiving treatment is approaching that of

the general population. With effective treatment, HIV has been transformed into a

chronic, manageable disease; consequently, more convenient, more tolerable and

less-toxic medications are critical for long-term adherence and clinical responses.

More recently, the development of new drugs in existing classes with activity against

drug-resistant virus (e.g., NNRTIs, PIs), and of drugs with new mechanisms of action

(HIV entry inhibitors, integrase inhibitors), has offered greatly improved treatment

options for individuals with treatment experience and/or drug-resistant viral strains.

Newer compounds and strategies continue to be tested and will ensure further

progress in the field. The concomitant treatment of HIV infection and TB is

complicated by overlapping drug toxicities, drug–drug interactions, and the inconvenience of multidrug regimens. However, effective comanagement strategies are

possible, and clinical trials are either planned or under way to ensure further progress

in this area.


1 Lohse, N., Hansen, A.B., Pedersen, G.,

Romberg, G., Gestalt, J., Sorensen, H.T.,

Viet, M. and Nobel, N. (2007) Survival of

persons with and without HIV infection in

Denmark, 1995–2005. Ann. Intern. Med.,

146, 87–95.

2 Bhaskaran, K., Hamouda, O., Sannes, M.,

Boufassa, F., Johnson, A.M., Lambert, P.C.,

Porter, K., CASCADE Collaboration (2008)

Changes in the risk of death after HIV

seroconversion compared with mortality in

the general population. JAMA, 300, 51–59.

3 Fischl, M.A., Richman, D.D., Grieco,

M.H., Gottlieb, M.S., Volberding, P.A.,

Laskin, O.L., Leedom, J.M. et al. (1987) The

efficacy of azidothymidine (AZT) in the

treatment of patients with AIDS and AIDSrelated complex. A double-blind, placebocontrolled trial. N. Engl. J. Med., 317,


4 Richman, D.D., Fischl, M.A., Grieco,

M.H., Gottlieb, M.S., Volberding, P.A.,

Laskin, O.L., Leedom, J.M. et al. (1987) The

toxicity of azidothymidine (AZT) in the

treatment of patients with AIDS and AIDSrelated complex. A double-blind, placebocontrolled trial. N. Engl. J. Med., 317,



j 4 HIV/AIDS Drugs


5 Collier, A.C., Bozzette, S., Coombs, R.W.,

Causey, D.M., Schoenfeld, D.A., Spector,

S.A., Pettinelli, C.B. et al. (1990) A pilot

study of low-dose zidovudine in human

immunodeficiency virus infection. N.

Engl. J. Med., 323, 1015–1021.

6 Volberding, P.A., Lagakos, S.W., Koch,

M.A., Pettinelli, C., Myers, M.W., Booth,

D.K., Balfour, H.H. Jr et al. (1990)

Zidovudine in asymptomatic human

immunodeficiency virus infection. A

controlled trial in persons with fewer than

500 CD4-positive cells per cubic

millimetre. The AIDS Clinical Trials

Group of the National Institute of Allergy

and Infectious Diseases. N. Engl. J. Med.,

322, 941–949.

7 Gallant, J.E., DeJesus, E., Arribas, J.R.,

Pozniak, A.L., Gazzard, B., Campo, R.E.,

Lu, B. et al., Study 934 Group (2006)

Tenofovir DF, emtricitabine, and efavirenz

vs. zidovudine, lamivudine, and efavirenz

for HIV. N. Engl. J. Med., 354, 251–260.

8 Hammer, S.M., Katzenstein, D.A.,

Hughes, M.D., Gundacker, H., Schooley,

R.T., Haubrich, R.H., Henry, W.K. and the

AIDS Clinical Trials Group Study 175

Study Team (1996) A trial comparing

nucleoside monotherapy with

combination therapy in HIV-infected

adults with CD4 cell counts from 200 to

500 per cubic millimetre. N. Engl. J. Med.,

335, 1081–1090.

9 Delta Coordinating Committee (1996)

Delta: a randomised double-blind

controlled trial comparing combinations

of zidovudine plus didanosine or

zalcitabine with zidovudine alone in

HIV-infected individuals. Lancet, 348,


10 Saravolatz, L.D., Winslow, D.L., Collins,

G., Hodges, J.S., Pettinelli, C., Stein, D.S.,

Markowitz, N. and the Investigators for the

Terry Beirn Community Programs for

Clinical Research on AIDS (1996)

Zidovudine alone or in combination with

didanosine or zalcitabine in HIV-infected

patients with the acquired

immunodeficiency syndrome or fewer








than 200 CD4 cells per cubic millimetre. N.

Engl. J. Med., 335, 1099–1106.

Havlir, D.V., Tierney, C., Friedland, G.H.,

Pollard, R.B., Smeaton, L., Sommadossi,

J.P., Fox, L. et al. (2000) In vivo antagonism

with zidovudine plus stavudine

combination therapy. J. Infect. Dis., 182,


Bartlett, J.A., Benoit, S.L., Johnson, V.A.,

Quinn, J.B., Sepulveda, G.E., Ehmann,

W.C., Tsoukas, C. and the North American

HIV Working Party (1996) Lamivudine

plus zidovudine compared with

zalcitabine plus zidovudine in patients

with HIV infection. A randomized,

double-blind, placebo-controlled trial.

Ann. Intern. Med., 125, 161–172.

Eron, J.J., Benoit, S.L., Jemsek, J.,

MacArthur, R.D., Santana, J., Quinn, J.B.,

Kuritzkes, D.R. and the North American

HIV Working Party (1995) Treatment with

lamivudine, zidovudine, or both in HIVpositive patients with 200 to 500 CD4 ỵ

cells per cubic millimetre. N. Engl. J. Med.,

333, 1662–1669.

DeJesus, E., Herrera, G., Teofilo, E.,

Gerstoft, J., Buendia, C.B., Brand, J.D.,

Brothers, C.H. and the CNA30024 Study

Team (2004) Abacavir versus zidovudine

combined with lamivudine and efavirenz,

for the treatment of antiretroviral-naive

HIV-infected adults. Clin. Infect. Dis., 39,


Mallal, S., Phillips, E., Carosi, G., Molina,

J.M., Workman, C., Tomazic, J., J€agelGuedes, E. and the PREDICT-1 Study

Team (2008) HLA-BÃ 5701 screening for

hypersensitivity to abacavir. N. Engl. J.

Med., 358, 568–579.

Sabin, C.A., Worm, S.W., Weber, R., Reiss,

P., El-Sadr, W., Dabis, F., De Wit, S. and the

D:A:D Study Group (2008) Use of

nucleoside reverse transcriptase inhibitors

and risk of myocardial infarction in HIVinfected patients enrolled in the D:A:D

study: a multi-cohort collaboration. Lancet,

371, 1417–1426.

Strategies for Management of AntiRetroviral Therapy/INSIGHT; DAD Study








Groups (2008) Use of nucleoside reverse

transcriptase inhibitors and risk of

myocardial infarction in HIV-infected

patients. AIDS, 22, F17–F24

Sax, P., Tierney, C., Collier, A., Fischl, M.,

Godfrey, C., Jahed, N. et al. (2008) ACTG

5202: shorter time to virologic failure (VF)

with abacavir/lamivudine (ABC/3TC) than

tenofovir/emtricitabine (TDF/FTC) as part

of combination therapy in treatment-na€ıve

subjects with screening HIV RNA

!100,000 c/ml. In Programs and Abstracts

of the XVII International AIDS

Conference, Mexico City, August 3–8,

abstract #THAB0303.

Schooley, R.T., Ruane, P., Myers, R.A.,

Beall, G., Lampiris, H., Berger, D., Chen,

S.S., Miller, M.D. and the Study 902 Team

(2002) Tenofovir DF in antiretroviralexperienced patients: results from a 48week, randomized, double-blind study.

AIDS, 16, 1257–1263.

Panel on Clinical Practices for the

Treatment of HIV Infection. Guidelines

for the use of antiretroviral agents in

HIV-infected adults and adolescents.

www.aids.info.org. November 3, 2008


Hammer, S.M., Eron, J.J. Jr, Reiss, P. et al.

(2008) Antiretroviral treatment of adult

HIV infection: 2008 recommendations of

the International AIDS Society-USA panel.

JAMA, 300, 555–570.

Gulick, R.M., Ribaudo, H.J., Shikuma,

C.M., Lustgarten, S., Squires, K.E., Meyer,

W.A. 3rd, Acosta, E.P. and the AIDS

Clinical Trials Group Study A5095 Team

(2004) Triple-nucleoside regimens versus

efavirenz-containing regimens for the

initial treatment of HIV-1 infection. N.

Engl. J. Med., 350, 1850–1861.

Moyle, G., Higgs, C., Teague, A., Mandalia,

S., Nelson, M., Johnson, M., Fisher, M. and

Gazzard, B. (2006) An open-label,

randomized comparative pilot study of a

single-class quadruple therapy regimen

versus a 2-class triple therapy regimen for

individuals initiating antiretroviral

therapy. Antivir. Ther., 11, 73–78.

24 Weinstock, H.S., Zaidi, I., Heneine, W.,

Bennett, D., Garcia-Lerma, J.G., Douglas,

J.M. Jr, LaLota, M. et al. (2004) The

epidemiology of antiretroviral drug

resistance among drug-na€ıve HIV-1infected persons in 10 US cities. J. Infect.

Dis., 189, 2174–2180.

25 Richman, D.D., Havlir, D., Corbeil, J.,

Looney, D., Ignacio, C., Spector, S.A.,

Sullivan, J. et al. (1994) Nevirapine

resistance mutations of human

immunodeficiency virus type 1 selected

during therapy. J. Virol., 68, 1660–1666.

26 D’Aquila, R.T., Hughes, M.D., Johnson,

V.A., Fischl, M.A., Sommadossi, J.P., Liou,

S.H., Timpone, J. and the National

Institute of Allergy and Infectious

Diseases AIDS Clinical Trials Group

Protocol 241 Investigators (1996)

Nevirapine, zidovudine, and didanosine

compared with zidovudine and didanosine

in patients with HIV-1 infection, A

randomized, double-blind, placebocontrolled trial. Ann. Intern. Med., 124,


27 Montaner, J.S., Reiss, P., Cooper, D., Vella,

S., Harris, M., Conway, B., Wainberg, M.A.

et al. (1998) A randomized, double-blind

trial comparing combinations of

nevirapine, didanosine, and zidovudine

for HIV-infected patients: the INCAS

(Italy, The Netherlands, Canada and

Australia Study) Trial. JAMA, 279,


28 Baylor, M.S. and Johann-Liang, R. (2004)

Hepatotoxicity associated with nevirapine

use. J. Acquir. Immune Defic. Syndr., 35,


29 Boulle, A., Van Cutsem, G., Cohen, K.,

Hilderbrand, K., Mathee, S., Abrahams, M.

et al. (2008) Outcomes of nevirapine- and

efavirenz-based antiretroviral therapy

when coadministered with rifampicinbased antitubercular therapy. JAMA, 300,


30 Staszewski, S., Morales-Ramirez, J.,

Tashima, K.T., Rachlis, A., Skiest, D.,

Stanford, J., Stryker, R. et al. (1999)

Efavirenz plus zidovudine and


j 4 HIV/AIDS Drugs








lamivudine, efavirenz plus indinavir, and

indinavir plus zidovudine and lamivudine

in the treatment of HIV-1 infection in

adults, Study 006 Team. N. Engl. J. Med.,

341, 1865–1873.

Clifford, D.B., Evans, S., Yang, Y., Acosta,

E.P., Goodkin, K., Tashima, K., Simpson,

D. et al. (2005) Impact of efavirenz on

neuropsychological performance and

symptoms in HIV-infected individuals.

Ann. Intern. Med., 143, 714–721.

Madruga, J.V., Cahn, P., Grinsztejn, B.,

Haubrich, R., Lalezari, J., Mills, A., Pialoux,

G. and the DUET-1 study group (2007)

Efficacy and safety of TMC125 (etravirine)

in treatment-experienced HIV-1-infected

patients in DUET-1: 24-week results from a

randomised, double-blind, placebocontrolled trial. Lancet, 370, 29–38.

Lazzarin, A., Campbell, T., Clotet, B.,

Johnson, M., Katlama, C., Moll, A.,

Towner, W. and the DUET-2 study group

(2007) Efficacy and safety of TMC125

(etravirine) in treatment-experienced HIV1-infected patients in DUET-2: 24-week

results from a randomised, double-blind,

placebo-controlled trial. Lancet, 370,


Palella, F.J. Jr, Delaney, K.M., Moorman,

A.C., Loveless, M.O., Fuhrer, J., Satten,

G.A., Aschman, D.J. and Holmberg, S.D.

(1998) Declining morbidity and mortality

among patients with advanced human

immunodeficiency virus infection.

N. Engl. J. Med., 338, 853–860.

Cameron, D.W., Heath-Chiozzi, M.,

Danner, S., Cohen, C., Kravcik, S.,

Maurath, C., Sun, E. and The Advanced

HIV Disease Ritonavir Study Group (1998)

Randomised placebo-controlled trial of

ritonavir in advanced HIV-1 disease.

Lancet, 351, 543–549.

Gulick, R.M., Mellors, J.W., Havlir, D.,

Eron, J.J., Gonzalez, C., McMahon, D.,

Richman, D.D. et al. (1997) Treatment with

indinavir, zidovudine, and lamivudine in

adults with human immunodeficiency

virus infection and prior antiretroviral

therapy. N. Engl. J. Med., 337, 734–739.

37 Hammer, S.M., Squires, K.E., Hughes,

M.D., Grimes, J.M., Demeter, L.M.,

Currier, J.S., Eron, J.J. Jr, and the AIDS

Clinical Trials Group 320 Study Team

(1997) A controlled trial of two nucleoside

analogues plus indinavir in persons with

human immunodeficiency virus infection

and CD4 cell counts of 200 per cubic

millimeter or less. N. Engl. J. Med., 337,


38 Saag, M.S., Tebas, P., Sension, M., Conant,

M., Myers, R., Chapman, S.K., Anderson,

R., Clendeninn, N., and the Viracept

Collaborative Study Group (2001)

Randomized, double-blind comparison of

two nelfinavir doses plus nucleosides in

HIV-infected patients (Agouron study

511). AIDS, 15, 1971–1978.

39 Murphy, R.L., Brun, S., Hicks, C., Eron,

J.J., Gulick, R., King, M., White, A.C. Jr.

et al. (2001) ABT 378/ritonavir plus

stavudine and lamivudine for the

treatment of antiretroviral-naive adults

with HIV-1 infection: 48-week results.

AIDS, 15, F1–F9.

40 Benson, C.A., Deeks, S.G., Brun, S.C.,

Gulick, R.M., Eron, J.J., Kessler, H.A.,

Murphy, R.L. et al. (2002) Safety and

antiviral activity at 48 weeks of lopinavir/

ritonavir plus nevirapine and 2 nucleoside

reverse-transcriptase inhibitors in human

immunodeficiency virus type 1-infected

protease inhibitor-experienced patients.

J. Infect. Dis., 185, 599–607.

41 Walmsley, S., Bernstein, B., King, M.,

Arribas, J., Beall, G., Ruane, P., Johnson,

M. and the M98-863 Study Team (2002)

Lopinavir-ritonavir versus nelfinavir for

the initial treatment of HIV infection.

N. Engl. J. Med., 346, 2039–2046.

42 Riddler, S.A., Haubrich, R., DiRienzo,

A.G., Peeples, L., Powderly, W.G.,

Klingman, K.L., Garren, K.W. and the

AIDS Clinical Trials Group Study A5142

Team (2008) Class-sparing regimens for

initial treatment of HIV-1 infection.

N. Engl. J. Med., 358, 2095–2106.

43 Haubrich, R.H., Riddler, S., DiRienzo, G.,

Komarow, L., Powderly, W.G., Klingman,







K., Garren, K.W., et al., and the AIDS

Clinical Trials Group (ACTG) A5142 Study

Team (2009) Metabolic outcomes in a

randomized trial of nucleoside,

nonnucleoside and protease inhibitorsparing regimens for initial HIV

treatment, AIDS, 23,1109–18.

Squires, K., Lazzarin, A., Gatell, J.M.,

Powderly, W.G., Pokrovskiy, V., Delfraissy,

J.F., Jemsek, J. et al. (2004) Comparison of

once-daily atazanavir with efavirenz, each

in combination with fixed-dose zidovudine

and lamivudine, as initial therapy for

patients infected with HIV. J. Acquir.

Immune Defic. Syndr., 36, 1011–1019.

Molina, J.M., Andrade-Villanueva, J.,

Echevarria, J., Chetchotisakd, P., Corral, J.,

David, N., Moyle, G. and the CASTLE

Study Team (2008) Once-daily atazanavir/

ritonavir versus twice-daily lopinavir/

ritonavir, each in combination with

tenofovir and emtricitabine, for

management of antiretroviral-naive HIV1-infected patients: 48 week efficacy and

safety results of the CASTLE study. Lancet,

372, 646–655.

Johnson, M., Grinsztejn, B., Rodriguez, C.,

Coco, J., DeJesus, E., Lazzarin, A.,

Lichtenstein, K. et al. (2005) Atazanavir

plus ritonavir or saquinavir, and lopinavir/

ritonavir in patients experiencing multiple

virological failures. AIDS, 19, 685–694.

Eron, J.J. Jr, Yeni, P., Gathe, J. Jr, Estrada,

V., DeJesus, E., Staszewski, S., Lackey, P.

and the KLEAN study team (2006) The

KLEAN study of fosamprenavir-ritonavir

versus lopinavir-ritonavir, each in

combination with abacavir-lamivudine, for

initial treatment of HIV infection over 48

weeks: a randomised non-inferiority trial.

Lancet, 368, 476–482.

Hicks, C.B., Cahn, P., Cooper, D.A.,

Walmsley, S.L., Katlama, C., Clotet, B.,

Lazzarin, A. and the RESIST investigator

group (2006) Durable efficacy of tipranavirritonavir in combination with an

optimized background regimen of

antiretroviral drugs for treatmentexperienced HIV-1-infected patients at 48








weeks in the Randomized Evaluation of

Strategic Intervention in multi-drug

resistant patients with Tipranavir

(RESIST) studies: an analysis of combined

data from two randomised open-label

trials. Lancet, 368, 466–475.

Katlama, C., Esposito, R., Gatell, J.M.,

Goffard, J.C., Grinsztejn, B., Pozniak, A.,

Rockstroh, J. and the POWER 1 study

group (2007) Efficacy and safety of

TMC114/ritonavir in treatmentexperienced HIV patients: 24-week results

of POWER 1. AIDS, 21, 395–402.

Haubrich, R., Berger, D., Chiliade, P.,

Colson, A., Conant, M., Gallant, J. et al.

(2007) Week 24 efficacy and safety of

TMC114/ritonavir in treatmentexperienced HIV patients: POWER 2.

AIDS, 21, F11–18.

Madruga, J.V., Berger, D., McMurchie, M.,

Suter, F., Banhegyi, D., Ruxrungtham, K.,

Norris, D. and the TITAN study group

(2007) Efficacy and safety of darunavirritonavir compared with that of lopinavirritonavir at 48 weeks in treatmentexperienced, HIV-infected patients in

TITAN: a randomised controlled phase III

trial. Lancet, 370, 49–58.

Ortiz, R., Dejesus, E., Khanlou, H.,

Voronin, E., van Lunzen, J., AndradeVillanueva, J., Fourie, J. et al. (2008)

Efficacy and safety of once-daily darunavir/

ritonavir versus lopinavir/ritonavir in

treatment-naive HIV-1-infected patients at

week 48. AIDS, 22, 1389–1397.

Moore, J.P. and Doms, R.W. (2003) The

entry of entry inhibitors: a fusion of

science and medicine. Proc. Natl Acad. Sci.

USA, 100, 10598–10602.

Lalezari, J.P., Henry, K., O’Hearn, M.,

Montaner, J.S., Piliero, P.J., Trottier, B.,

Walmsley, S. and the TORO 1 Study Group

(2003) Enfuvirtide, an HIV-1 fusion

inhibitor, for drug-resistant HIV infection

in North and South America. N. Engl. J.

Med., 348, 2175–2185.

Lazzarin, A., Clotet, B., Cooper, D., Reynes,

J., Arasteh, K., Nelson, M., Katlama, C. and

the TORO 2 Study Group (2003) Efficacy of


j 4 HIV/AIDS Drugs









enfuvirtide in patients infected with drugresistant HIV-1 in Europe and Australia.

N. Engl. J. Med., 348, 2186–2195.

Dorr, P., Westby, M., Dobbs, S., Griffin, P.,

Irvine, B., Macartney, M., Mori, J. et al.

(2005) Maraviroc (UK-427,857), a potent,

orally bioavailable, and selective smallmolecule inhibitor of chemokine receptor

CCR5 with broad-spectrum anti-human

immunodeficiency virus type 1 activity.

Antimicrob. Agents Chemother., 49,


Gulick, R.M., Lalezari, J., Goodrich, J.,

Clumeck, N., DeJesus, E., Horban, A.,

Nadler, J. et al. (2008) Maraviroc for

previously treated patients with R5 HIV-1

infection. N. Engl. J. Med., 359, 1429–1441.

Glass, W.G., McDermott, D.H., Lim, J.K.,

Lekhong, S., Yu, S.F., Frank, W.A., Pape, J.

et al. (2006) CCR5 deficiency increases risk

of symptomatic West Nile virus infection.

J. Exp. Med., 203, 35–40.

Nichols, W.G., Steel, H.M., Bonny, T.,

Adkison, K., Curtis, L., Millard, J., Kabeya,

K. and Clumeck, N. (2008) Hepatotoxicity

observed in clinical trials of aplaviroc

(GW873140). Antimicrob. Agents

Chemother., 52, 858–865.

Gulick, R.M., Su, Z., Flexner, C., Hughes,

M.D., Skolnik, P.R., Wilkin, T.J., Gross, R.

and the AIDS Clinical Trials Group 5211

Team (2007) Phase 2 study of the safety

and efficacy of vicriviroc, a CCR5

inhibitor, in HIV-1-Infected, treatmentexperienced patients. J. Infect. Dis., 196,


Hazuda, D.J., Felock, P., Witmer, M.,

Wolfe, A., Stillmock, K., Grobler, J.A.,

Espeseth, A. et al. (2000) Inhibitors of

strand transfer that prevent integration

and inhibit HIV-1 replication in cells.

Science, 287, 646–650.

Steigbigel, R.T., Cooper, D.A., Kumar,

P.N., Eron, J.J., Schechter, M., Markowitz,

M., Loutfy, M.R. and the BENCHMRK

Study Teams (2008) Raltegravir with

optimized background therapy for

resistant HIV-1 infection. N. Engl. J. Med.,

359, 339–354.

63 Cooper, D.A., Steigbigel, R.T., Gatell, J.M.,

Rockstroh, J.K., Katlama, C., Yeni, P.,

Lazzarin, A. and the BENCHMRK Study

Teams (2008) Subgroup and resistance

analyses of raltegravir for resistant HIV-1

infection. N. Engl. J. Med., 359, 355–365.

64 Markowitz, M., Nguyen, B.Y., Gotuzzo, E.,

Mendo, F., Ratanasuwan, W., Kovacs, C.,

Prada, G. and the Protocol 004 Part II

Study Team (2007) Rapid and durable

antiretroviral effect of the HIV-1 Integrase

inhibitor raltegravir as part of combination

therapy in treatment-naive patients with

HIV-1 infection: results of a 48-week

controlled study. J. Acquir. Immune Defic.

Syndr., 46, 125–133.

65 Lennox, J., Dejesus, E., Lazzarin, A.,

Pollard, R., Madruga, J., Zhao, J. et al.

(2008) STARTMRK, A Phase III study of

the safety & efficacy of raltegravir (RAL)based vs. efavirenz (EFV)-based

combination therapy in treatment-naive

HIV-infected patients. In Program and

Abstracts of the 48th International

Conference on Antimicrobial Agents and

Chemotherapy (ICAAC) and the

Infectious Diseases Society of America

(IDSA) 46th Annual Meeting, Washington,

DC, October 25–28, Abstract H-896a.

66 Santoscoy, M., Cahn, P., Gonzalez, C.,

Hao, W., Pozniak, A., Shalit, P., Vanveggel,

S., Boven, K. et al. (2008) TMC278

(rilpivirine), a next-generation NNRTI,

demonstrates long-term efficacy and

tolerability in ARV-na€ıve patients: 96-week

results of study C204. In Programs and

Abstracts of the XVII International AIDS

Conference, Mexico City, August 38,

abstract #TUAB0103.

67 Baert, L.,vant Klooster, G., Dries, W.,

Franỗois, M., Wouters, A., Basstanie, E.,

Iterbeke, K., et al. (2009) Development of a

long-acting injectable formulation with

nanoparticles of rilpivirine (TMC 278) for

HIV treatment, Eur. J. Pharm. Biopharm.,

72, 502–508.

68 Saag, M., Ive, P., Heera, J., Tawadrous, M.,

DeJesus, E., Clumeck, N., Cooper, D. et al.

(2007) A multicenter, randomized, double-


blind, comparative trial of a novel CCR5

antagonist, maraviroc versus efavirenz,

both in combination with Combivir

(zidovudine [ZDV]/lamivudine [3TC]), for

the treatment of antiretroviral naive

subjects infected with R5 HIV-1: week 48

results of the MERIT study. In Programs

and Abstracts of the 4th International

AIDS Conference on Pathogenesis,

Treatment, and Prevention, Sydney,

Australia, July 22–25, abstract #WESS104.

69 Markowitz, M., Nguyen, B.-Y., Gotuzzo,

E., Mendo, F., Ratanasuwan, W., Kovacs,

C., Wan, H. et al. (2008) Sustained

antiretroviral efficacy of raltegravir as

part of combination ART in treatmentnaive HIV-1 infected patients: 96-week

data. In Programs and Abstracts of the

XVII International AIDS Conference,

Mexico City, August 3–8, abstract


70 Blanc, F.X., Havlir, D.V., Onyebujoh, P.C.,

Thim, S., Goldfeld, A.E. and Delfraissy, J.F.

(2007) Treatment strategies for HIVinfected patients with tuberculosis:

ongoing and planned clinical trials.

J. Infect. Dis., 196 (Suppl. 1), S46–S51


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