Multiresistant Virus Research Articles

Lenacapavir for the Treatment of Heavily Treatment-experienced People with Multi-class Resistant HIV

Multidrug resistance to antiretroviral therapy, while uncommon, is associated with high rates of clinical progression and virologic failure. Lenacapavir is the first capsid inhibitor to be approved for the treatment of HIV infection in heavily treatment-experienced people with multi-resistant virus, who cannot be successfully treated with other available therapies due to resistance, intolerance or safety considerations. The key feature of lenacapavir is its long half-life, which allows its subcutaneous formulation to be administered every 6 months. This is crucial for a population with low adherence rates to antiretroviral therapy. This review discusses the characteristics of lenacapavir, including its mechanism of action, pharmacokinetics/pharmacodynamics and resistance profile, the key efficacy and safety data from clinical trials, and its place in the management of patients with multidrug-resistant HIV infection.

The Mosaico HIV Vaccine Study: A Step Back or a Stepping Stone for Future Vaccine Development?

Multidrug resistance to antiretroviral therapy, while uncommon, is associated with high rates of clinical progression and virologic failure. Lenacapavir is the first capsid inhibitor to be approved for the treatment of HIV infection in heavily treatment-experienced people with multi-resistant virus, who cannot be successfully treated with other available therapies due to resistance, intolerance or safety considerations. The key feature of lenacapavir is its long half-life, which allows its subcutaneous formulation to be administered every 6 months. This is crucial for a population with low adherence rates to antiretroviral therapy. This review discusses the characteristics of lenacapavir, including its mechanism of action, pharmacokinetics/pharmacodynamics and resistance profile, the key efficacy and safety data from clinical trials, and its place in the management of patients with multidrug-resistant HIV infection.

Synthesis, virtual screening and computational approach of a quinoxaline derivative as potent anti-HIV agent targeting the reverse transcriptase enzyme

Infection by the human immunodeficiency virus still represents a continuous serious concern and a global threat to human health. Due to the appearance of multi-resistant virus strains and the serious adverse side effects of the antiretroviral therapy administered, there is an urgent need for the development of new treatment agents that are more active, less toxic, and with increased tolerability to mutations. Quinoxaline derivatives are a class of heterocyclic compounds with a wide range of organic and remedial applications. In addition, they are known to significantly inhibit HIV reverse transcriptase (RT) and HIV replication in cell cultures. For these reasons, we are investigating the synthesis and computational studies of quinoxaline derivatives with a focus on their effects on the HIV RT enzyme, and we present here the structure of one such molecule, methyl 2-[(2E)-3-oxo-1,2,3,4-tetrahydroquinoalin-2-ylidene] acetate, which was confirmed by X-ray diffraction studies. In the crystal, N—H···O and C—H···O hydrogen bonds form ribbons whose mean planes are inclined to (111) by 25.69(8)°. The ribbons are formed into stacks by C—H···π(ring) interactions and π-stacking interactions between carbonyl groups. The Hirshfeld surface map allows us to understand the nature of interactions in the contribution to crystal packing. A density functional theory (DFT) calculation was performed to optimize the geometrical parameters and then they were compared with the solid-state phase. The molecular electrostatic potential map displays reactive sites on the surface, which are responsible for intermolecular interaction in the chemical species. Computational molecular docking, in addition to molecular dynamics simulations and MMGB/PBSA binding energy techniques, was used to assess the affinity of the molecule for the HIV reverse transcriptase enzyme. The new quinoxaline derivative is more powerful in terms of binding affinity and binding conformation stability with the HIV reverse transcriptase enzyme, which suggests the molecule is a good candidate for further biological optimization. Communicated by Ramaswamy H. Sarma

Design, synthesis and biological evaluation of quinoxaline compounds as anti-HIV agents targeting reverse transcriptase enzyme

Infection by human immunodeficiency virus still represents a continuous serious concern and a global threat to human health. Due to appearance of multi-resistant virus strains and the serious adverse side effects of the antiretroviral therapy administered, there is an urgent need for the development of new treatment agents, more active, less toxic and with increased tolerability to mutations. Quinoxaline derivatives are an emergent class of heterocyclic compounds with a wide spectrum of biological activities and therapeutic applications. These types of compounds have also shown high potency in the inhibition of HIV reverse transcriptase and HIV replication in cell culture. For these reasons we propose, in this work, the design, synthesis and biological evaluation of quinoxaline derivatives targeting HIV reverse transcriptase enzyme. For this, we first carried out a structure-based development of target-specific compound virtual chemical library of quinoxaline derivatives. The rational construction of the virtual chemical library was based on previously assigned pharmacophore features. This library was processed by a virtual screening protocol employing molecular docking and 3D-QSAR. Twenty-five quinoxaline compounds were selected for synthesis in the basis of their docking and 3D-QSAR scores and chemical synthetic simplicity. They were evaluated as inhibitors of the recombinant wild-type reverse transcriptase enzyme. Finally, the anti-HIV activity and cytotoxicity of the synthesized quinoxaline compounds with highest reverse transcriptase inhibitory capabilities was evaluated. This simple screening strategy led to the discovery of two selective and potent quinoxaline reverse transcriptase inhibitors with high selectivity index.

Efficacy and safety of alisporivir for the treatment of hepatitis C infection

ABSTRACTIntroduction: Alisporivir (ALV) (previously known as Debio 025) is a potent, pangenotypic host-targeting antiviral oral agent acting on cyclophilin A, which is necessary for HCV replication.Areas covered: This article reviews the therapeutic efficacy and safety of ALV for the treatment of HCV infection.Expert opinion: Direct-acting antivirals (DAAs) have revolutionized the HCV antiviral treatment paradigm with success rates well above 95% for all HCV genotypes. However, challenges still remain in certain patient populations such as those who have developed resistance and have experienced multi-DAA failure. To cure HCV infection, a treatment regimen must combine antiviral potency and a high barrier to resistance. ALV fulfills this need as shown by the studies evaluating its clinical efficacy. Nevertheless, ALV missed the chance to be included in the HCV treatment armamentarium after the FDA halted clinical studies following reports of serious side effects (three cases of pancreatitis, one lethal). However, it is possible that ALV could still be considered for HCV-infected non-cirrhotic patients that are infected with a multiresistant virus or with HCV genotype 3, although it must be said that the drug industry would be reluctant to invest in new antivirals if the current clinical need is effectively met.

A New Mechanism of Resistance of Human Immunodeficiency Virus Type 2 to Integrase Inhibitors: A 5-Amino-Acid Insertion in the Integrase C-Terminal Domain.

Integrase strand transfer inhibitors (INSTIs) are crucial for the treatment of human immunodeficiency virus (HIV) type 2 infection, due to limited available therapeutic options. Recently, bictegravir has been approved for HIV-1, but no data are currently available for HIV-2. We assessed the phenotypic susceptibility of 12 HIV-2 clinical isolates, obtained from 2 antiretroviral-naive and 10 antiretroviral-experienced patients, to 5 INSTIs (bictegravir, cabotegravir, dolutegravir, elvitegravir, and raltegravir) at the virological failure of an INSTI-based regimen. The 50% inhibitory concentrations (IC50s) were determined. Phenotypic inhibitory quotients were determined using trough INSTI plasma concentrations. Wild-type viruses were susceptible to the 5 INSTIs, with IC50s in the nanomolar range. Bictegravir had a lower IC50 than the other INSTIs on those HIV-2 isolates bearing major, resistance-associated mutations (codons 143, 148, and 155). We identified a new resistance profile-a 5-amino-acid insertion at codon 231 of the HIV-2 integrase (231INS)-in 6 patients at the virological failure of a raltegravir-based regimen. Those patients had adequate raltegravir concentrations, but harbored multiresistant viruses with low genotypic susceptibility scores (median = 1.5). This insertion rendered isolates highly resistant to raltegravir and elvitegravir, and moderately resistant to dolutegravir and cabotegravir. Regarding bictegravir, 2 isolates remained susceptible and 2 had a slight increase in IC50 (3- to 5-fold change). Our results confirm the potency of INSTI on HIV-2 clinical isolates with wild-type integrase. In addition, we identified a new resistance pathway, 231INS, selected in antiretroviral-experienced patients with multiresistant HIV-2 viruses. This highlights the need of close follow-up of those patients initiating an INSTI-based regimen.

Highly frequent HIV-1 minority resistant variants at baseline of the ANRS 139 TRIO trial had a limited impact on virological response.

To assess the prevalence of minority resistant variants (MRVs) at baseline and their impact on the virological response. The ANRS 139 TRIO trial evaluated the combination of raltegravir, etravirine and darunavir, plus an optimized background therapy, in 87% of cases. Patients were highly experienced and harboured multiresistant viruses, but were naive to the three drugs, and showed a high level of virological suppression. Ultra-deep sequencing of reverse transcriptase, protease and integrase regions was performed at the trial baseline, and sequences were interpreted according to the ANRS algorithm. MRVs were assessed using MiSeq and 454 technologies (limit of detection 1%). At baseline, minority variants with at least one NRTI, one NNRTI, one PI, one major PI or an integrase inhibitor resistance-associated mutation were present in 46%, 45%, 68%, 24% and 13% of patients, respectively. When minority variants are taken into account, the prevalence of resistance to etravirine, darunavir and raltegravir at baseline was 29%, 40% and 9%, respectively. No difference was observed in the prevalence of MRVs between patients with virological failure and those with virological success, except a trend for patients exhibiting baseline etravirine MRVs (50% versus 26%, P = 0.09). We have shown a high level of MRVs at baseline in highly pre-treated patients harbouring multiresistant viruses. However, these MRVs were not associated with an increased risk of virological failure, except for a trend for etravirine MRVs.

Lack of benefit of 3‐month intensification with enfuvirtide plus optimized background regimen (OBR) versus OBR alone in patients with multiple therapeutic failures: The INNOVE study

The objective of the present study was to evaluate the virological efficacy of a 3-month short-course intensification with enfuvirtide (ENF) associated with an optimized background regimen (OBR) in treatment-experienced patients infected with HIV-1 with multiple therapeutic failures. This was a prospective, randomized, open-label multicenter trial including patients infected with HIV-1 and harboring a multi-resistant virus that was still susceptible to at least 2 active compounds. Patients were randomized (1:1) to receive OBR + ENF or OBR alone. ENF was discontinued at Week 12. The primary endpoint was the proportion of patients with plasma viral load <50 copies/ml at Week 24. Fifteen patients were randomized into the OBR group and 14 into the OBR + ENF group with a median viral load of 4.1 log(10) copies/ml and a median CD4+ cell count of 346 cells/mm(3) . The primary endpoint was achieved in 93% (14/15) and 79% (11/14) of patients, respectively. Eighty-seven percent (13/15) of patients had a viral load <50 copies/ml as soon as Week 12 in the OBR group and 79% (11/14) in the OBR + ENF group. At Week 12, the median CD4+ cell count was 327 in the OBR and 437 in the OBR + ENF groups and at Week 24 they were comparable. Intensification with ENF had no significant impact on PBMCs HIV-DNA levels. A 3-month short-course intensified treatment with ENF did not improve Week-24 virological response in treatment-experienced patients infected with HIV-1 harboring resistant viruses that were still susceptible to two antiretroviral drugs.

Clinical Management of Treatment-Experienced, HIV/AIDS Patients in the Combination Antiretroviral Therapy Era

Despite the success of combination antiretroviral therapy (ART) in improving clinical outcomes, treatment failure remains a significant challenge, particularly for highly treatment-experienced patients. This review evaluates current issues in the management of HIV-infected, treatment-experienced patients. It may provide guidance in selecting active, tolerable drug combinations that promote a reasonable quality of life, full adherence and a durable treatment response. Current treatment guidelines and clinical trial data were reviewed to identify reasons for treatment failure and to summarize therapy options for treatment-experienced and highly treatment-experienced patients. Current treatment options include nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and inhibitors of viral fusion, entry and integration. The use of NRTIs may be limited by resistance and short- and long-term toxicities. Resistance has restricted the NNRTI class with cross-resistance preventing their sequential use. Etravirine, a next-generation NNRTI, however, demonstrates effective virological suppression in patients with baseline NNRTI resistance. Boosted PIs are key components of ART for treatment-experienced patients. The newer boosted PIs tipranavir and darunavir have demonstrated impressive activity in patients with resistance to NRTIs, NNRTIs and PIs, as well as in less treatment-experienced patients for darunavir. The fusion inhibitor enfuvirtide has demonstrated efficacy in heavily treatment-experienced patients, although injection-site reactions can be problematical. The recently approved integrase inhibitor raltegravir has also shown impressive potency and tolerability in highly treatment-experienced patients. Finally, the entry inhibitor maraviroc has also been approved recently, although its use is somewhat limited by the need for HIV tropism testing. The availability of potent next-generation PIs, NNRTIs, integrase and entry-inhibitors may offer improved therapy for treatment-experienced patients, including those with multiresistant virus. These new drugs may reduce HIV immunological and clinical progression and in doing so may also reduce treatment costs.

Enfuvirtide: from basic investigations to current clinical use

Importance of the field: Drug resistance is a major challenge in the treatment of HIV infection. Enfuvirtide is the first entry inhibitor to have been approved for clinical use.Areas covered in this review: Relevant information through searches of MEDLINE (1998 to June 2010) and meeting abstracts of major HIV/AIDS conferences (2003 – June 2010) using the search terms ‘enfuvirtide’, ‘T-20’ and ‘fusion inhibitor’.What the reader will gain: Enfuvirtide blocks HIV fusion to host cells. It works against the different HIV-1 variants but is not active against HIV-2. The recommended dosage of enfuvirtide is 90 mg b.i.d. subcutaneously. The two large Phase III pivotal clinical trials TORO 1 and 2 showed that enfuvirtide is an effective therapeutic option as rescue therapy in combination with other active antiretroviral drugs. Resistance to enfuvirtide is conferred by mutations in the HR1 region of gp41. Single and double mutations have been shown to result in high-level resistance to enfuvirtide. Postmarketing studies have been helpful to define more precisely the place of enfuvirtide in the sequence of antiretroviral therapy.Take home message: The emergence of new compounds and new classes of drugs, highly active against multiresistant virus but more convenient to administer than enfuvirtide, will probably prevent the extensive use of enfuvirtide. This drug remains attractive in some subgroups of patients because of its excellent systemic tolerance and the lack of interactions with the major cytochrome P450 isoenzymes.

Extended use of raltegravir in the treatment of HIV-1 infection: optimizing therapy

Raltegravir is the first licensed compound in 2007 of the new integrase inhibitor drug class. At the dose of 400 mg twice daily, raltegravir showed a potent antiviral action in antiretroviral-naïve patients when associated with tenofovir and emtricitabine. Raltegravir was also found to be highly active in antiretroviral-experienced patients with virological failure and displaying multiresistant virus, as shown with the BENCHMRK and ANRS 139 TRIO trials. Finally, the use of raltegravir was assessed in the context of a switch strategy in antiretroviral-experienced patients with virological success [human immunodeficiency virus type 1 (HIV-1) RNA below detection limit], highlighting the following mandatory criteria in this strategy: the nucleoside reverse transcriptase inhibitors associated with raltegravir have to be fully active. In the different studies, raltegravir had a favorable safety and tolerability profile. In the clinical situation a switch in virologically suppressed patients receiving a protease inhibitor, an improvement of the lipid profile was observed. Overall, when analyzing the Phase II and III trials together, only a few patients on raltegravir discontinued for adverse events. The development of resistance to raltegravir mainly involved three resistance mutations in integrase gene: Q148H/K/R, N155H, and Y143C/H/R. In conclusion, raltegravir improved the clinical management of HIV-1 infection both in antiretroviral-naïve and in antiretroviral-experienced patients.

Clinical, virological and immunological responses in Danish HIV patients receiving raltegravir as part of a salvage regimen.

Raltegravir is the first integrase inhibitor approved for treatment of HIV-infected patients harboring multiresistant viruses. From a Danish population-based nationwide cohort of HIV patients we identified the individuals who initiated a salvage regimen including raltegravir and a matched cohort of HIV-infected patients initiating HAART for the first time. We compared these two cohorts for virological suppression, gain in CD4 count, and time to first change of initial regimen. We identified 32 raltegravir patients and 64 HIV patients who initiated HAART for the first time in the period 1 January 2006 to 1 July 2009. The virological and immunological responses in the raltegravir patients were comparable to those seen in the control cohort. No patients in the two cohorts died and no patients terminated raltegravir treatment in the observation period. Time to first change of initial regimen was considerably shorter for HAART-naïve patients. We conclude that salvage regimens including raltegravir have high effectiveness in the everyday clinical setting. The effectiveness of the regimens is comparable to that observed for patients initiating HAART for the first time. The risk of change in the salvage regimens after initiation of raltegravir is low.

Mutation T74S in HIV-1 subtype B and C proteases resensitizes them to ritonavir and indinavir and confers fitness advantage

Several drug resistance and secondary mutations have been described in HIV-1 viruses from patients undergoing antiretroviral therapy. In this study, we assessed the impact of the protease substitution T74S on the phenotype and on the replicative fitness in HIV-1 subtypes B and C. HIV-1 molecular clones carrying subtype B or C proteases had these coding regions subjected to site-directed mutagenesis to include T74S alone or in combination with four known protease inhibitor (PI) primary drug resistance mutations. All clones were used in a phenotypic assay to evaluate their susceptibility to most commercially available PIs. The impact of T74S on virus fitness was also assessed for all viruses through head-to-head competitions and oligonucleotide ligation assays to measure the proportion of each virus in culture. Viruses of both subtypes carrying T74S did not have their susceptibility altered to any tested PI. Viruses with the four resistance mutations showed strong resistance to most PIs with fold changes ranging from 5 to 300 times compared with their wild-type counterparts. Surprisingly, the addition of T74S to the multiresistant clones restored their susceptibilities to indinavir and ritonavir and partially to lopinavir, close to those of wild-type viruses. Most 74S-containing viruses were more fit than their 74T counterparts. Our results suggest that T74S is not a major drug resistance mutation, but it resensitizes multiresistant viruses to certain PIs. T74S is a bona fide accessory mutation, restoring fitness of multidrug-resistant viruses in both subtypes B and C. T74S should be further studied in clinical settings and considered in drug resistance interpretation algorithms.

Osteitis

Grundsätzlich ist das Therapiekonzept bei akuten und chronischen Osteitiden mittlerweile allgemein anerkannt und verbreitet. Die Behandlung durch multiresistente Erreger verursachter Osteitiden (MRE-Osteitiden) verlangt allerdings eine Reihe zusätzlicher Maßnahmen, um den Therapieerfolg dauerhaft zu sichern. Je nach Übertragungsweg und Resistenzentwicklungsmechanismen sollten Patienten mit bestimmten multiresistenten Erregern [z. B. MRSA (methicillinresistente Staphylokokken), VRE (vancomycinresistente Enterokokken)] isoliert behandelt werden. Die Isolierung wiederum macht zusätzliche Maßnahmen, wie Schleusen, Eradikation/Dekontamination, psychologische Betreuung usw. notwendig. Insgesamt handelt es sich bei der MRE-Osteitis zwar noch um eine relativ seltene Erkrankung, deren Komplexizität und Dauer jedoch eine intensive, spezielle und interdisziplinäre Therapie erfordern, um den gewünschten Erfolg zu erzielen. Dies wird durch die eigenen statistischen Zahlen eindeutig belegt. So konnten in unserer Klinik z. B. die MRSA-Übertragungen auf Normalstationen von 2000–2007 von 50 auf 4 pro Jahr verringert werden, bei gleichzeitiger Zunahme der aufgenommenen MRSA-Patienten von 16 auf 92.

Potent Antiretroviral Effect of MK-0518, a Novel HIV-1 Integrase Inhibitor, in Patients With Triple-Class Resistant Virus

Grinsztejn B, Nguyen BY, Katlama C, et al. Presented at: the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy; September 27–30, 2006; San Francisco, CA. Abstract H-16706 PURPOSE OF THE STUDY. Although there are &amp;gt;20 antiretroviral agents available in developed countries, multiple factors limit the construction of combinations of drugs that are capable of effective viral suppression. New agents are clearly needed, particularly for individuals with limited options. MK-0518 is a member of a new class of antiretroviral agents, integrase inhibitors. The purpose of this study was to generate preliminary information on the potency of MK-0518 in the treatment of individuals with triple-class–resistant virus. STUDY POPULATION AND METHODS. There were 178 HIV-infected patients enrolled and assigned to 1 of 3 doses of MK-0518 or placebo. They were followed for 24 weeks, and antiretroviral responses were evaluated. RESULTS. MK-0518 showed remarkable potency at all doses tested. Approximately 60% of the patients who received active drug achieved &amp;lt;50 copies per mL of plasma HIV RNA. Strikingly, ∼50% of the individuals with no active agent left in their background regimens achieved undetectable viral loads. MK-0518 was generally well tolerated at all doses, with headache being the most frequent adverse effect. CONCLUSIONS. MK-0518 had remarkable potent antiretroviral activity in individuals with limited treatment options. The availability of this new class of antiretroviral drug will markedly enhance the options available for patients who are running out of options. REVIEWER COMMENTS. Abstracts presented at scientific meetings are usually not appropriate for a “best-articles-published” series. However, the impact of MK-0518 will be extraordinary. With 3 additional new drugs recently or soon to be available, we will soon have the ability to “salvage” patients with multiresistant virus.

Darunavir (TMC114): a new HIV-1 protease inhibitor

Effective combination therapy for HIV/AIDS is now available and has made a major impact on HIV-related mortality and morbidity. The effects of even the most active of antiretroviral drugs are hampered by drug resistance and tolerability issues. Darunavir (TMC114), coadministered with low-dose ritonavir (darunavir/r), is a new HIV-1 protease inhibitor that has been designed to be active against both wild-type and multi-resistant virus. Darunavir/r 600/100 mg b.i.d. in a combination antiretroviral regimen in the POWER trials has provided treatment-experienced patients with substantially greater virological and immunological benefits compared with standard of care. This article reviews the presently available data on darunavir, its pharmacology, pharmacokinetics, drug–drug interactions and clinical trial results, as well as examining darunavir from a health economic perspective.

14th Conference on Retroviruses and Opportunistic Infections (CROI 2007)

In the category ‘Best new drug’: raltegravir This integrase inhibitor was previously called MK-0518 and will have the trade name Isentress® (Merck). In Los Angeles, results from two Phase III trials, called Benchmrk 1 and 2, were presented. In both trials, patients with advanced HIV infection and multi-resistant viruses were recruited in the USA (Benchmrk 2) and in the rest of the world (Benchmrk 1) [1,2]. An optimal background treatment (OBT) was constructed with conventional drugs and resistance tests. To OBT, either placebo or raltegravir, 400 mg/twice daily, were added. Results from Benchmrck 1 are shown in Table 1. These are excellent results in such an advanced patient population; additional good news was the absence of any identifiable side effect that could plausibly be attributed to raltegravir, and a pharmacokinetic profile suggesting that drug interactions will be few. It is a safe bet that such a powerful drug will select resistance mutations; indeed, in patients from a Phase II study already presented at the Toronto Conference, two typical resistance mutations emerged, namely N155H and Q148H/K/S. With these results, submission to the US FDA will probably occur soon and approval, at least for advanced patients with multiresistance, might be granted as early as the second quarter of 2007. There are plans to use raltegravir earlier, in patients who have less-resistant virus or are even treatment naive. Studies in these patient populations are in progress. One handicap is the twicedaily administration, but pharmacokinetic data suggest that raltegravir will also be active once daily. Combination pills have proven to be very successful; we can anticipate that raltegravir will be paired with other new substances. In contrast to other new drugs such as darunavir or TMC-125 that, although effective, are more cubersome to use, raltegravir has a real chance to become part of the basic treatment regimen in most types of HIV-infected patients. A second integrase inhibitor formally called GS-9137 (Gilead) [2] has now morphed into elvitegravir. In contrast to raltegravir, it needs boosting by ritonavir, and is administrated once daily. In a Phase study, 20 mg/day was ineffective, whereas higher doses, particularly 125 mg/day combined with 100 mg of ritonavir, reduce viral load more than the background regimen (Table 2), without noticeable side effects. However, in cases where elvitegravir was the only active substance, resistance development was quite rapid.

Update on HAART in HIV

Highly active antiretroviral combination therapy (HAART) has been responsible for a dramatic decrease in AIDS mortality since 1996, and has changed the clinical profile of HIV infection from a sub-acute lethal to a chronic ambulatory disease. HAART consists of a double nucleoside (NRTI) backbone plus either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a ritonavir pharmacologically enhanced protease inhibitor (PI/r). Triple NRTI combinations are less potent than 2NRTIs/NNRTI or 2NRTIs/PI/r combinations. Antiretroviral first-line therapy is rapidly moving towards more convenient and less toxic regimens. Three double NRTI co-formulations are now available, and the risk of mitochondrial toxicity is low with drugs such as 3TC, FTC and tenofovir. Similarly, atazanavir, a recently available PI, can be given once daily and is less metabolically toxic than other PIs. Antiretroviral salvage therapy takes advantage of the development or availability of new drugs, either from existing (tipranavir, TMC 114 as new PIs) or new classes (T20 as a fusion inhibitor), that remain active on many triple-class drug resistant viruses. More progress is needed in the field of drug discovery, since a significant proportion of patients still die from AIDS with a multi-resistant virus, and since the incidence of primary HIV resistance is increasing in various parts of the world.