Showing papers in "Aids Reviews in 2003"

The immune reconstitution inflammatory syndrome.

Abstract: The use of highly active antiretroviral therapy (HAART) has led to a substantial decrease in the frequency of opportunistic infections among HIV-infected individuals, along with a significant reduction in their mortality rate. However, a subgroup of HAART-treated patients will exhibit paradoxical deterioration in their clinical status, despite satisfactory control of viral replication and improvements in CD4 lymphocyte counts. This clinical deterioration, known as the immune restoration syndrome or immune reconstitution inflammatory syndrome (IRIS), is a result of an exuberant inflammatory response towards previously diagnosed or incubating opportunistic pathogens, as well as responses towards other as yet undefined antigens. A variety of manifestations of IRIS have been described, most prominently including Mycobacterium avium complex lymphadenitis, paradoxical exacerbations of pulmonary and CNS Mycobacterium tuberculosis infection, paradoxical exacerbations of Cryptococcus neoformans meningitis and cytomegalovirus uveitis. Treatment for this disorder includes continuation of primary therapy against the offending pathogen in order to decrease the antigenic load, continuation of effective HAART, and judicious use of anti-inflammatory agents. Although the clinical manifestations of IRIS are sometimes dramatic, and result in substantial morbidity, the fact that these patients are capable of generating an inflammatory response allows many of them to ultimately discontinue secondary prophylaxis for the offending pathogen.

HIV Sequence Databases

Abstract: Two important databases are often used in HIV genetic research, the HIV Sequence Database in Los Alamos, which collects all sequences and focuses on annotation and data analysis, and the HIV RT/Protease Sequence Database in Stanford, which collects sequences associated with the development of viral resistance against anti-retroviral drugs and focuses on analysis of those sequences. The types of data and services these two databases offer, the tools they provide, and the way they are set up and operated are described in detail.

Predicting HIV-1 coreceptor usage with sequence analysis.

Abstract: Bioinformatics approaches are increasingly being used to identify and understand the genetic variation underlying changes in HIV-1 biological phenotype. The variable regions of the viral envelope are the major determinant of virus coreceptor usage and cell tropism. Specifically, amino acids 11 and 25 in the 3rd variable (V3) loop have been found to strongly influence viral syncytium inducing capacity and coreceptor usage. Many additional V3 loop changes, however, as well as changes elsewhere in Env, are thought to contribute to phenotype. In this review we describe several recently developed methods to analyze this variability and their use to predict biological phenotype based on sequence information. These approaches have identified changes in the V3 loop, in addition to the known changes at positions 11 and 25, that affect phenotype and significantly enhance our ability to predict phenotype from genotype. Besides improving phenotype prediction, methods that score V3 sequences on a continuous scale can also assist in the interpretation of evolutionary information about shifts in phenotype, and the relationship between that evolution and pathogenesis. Several examples and potential practical applications of this scoring are discussed. We conclude that advances in computational approaches have enhanced both our ability to predict and to understand HIV-1 biological phenotype evolution. Further development of these methods, by extending analysis to regions outside the V3 loop and to clades beyond subtype B, will extend our understanding of HIV-1 pathogenesis and inform treatment strategies.

Disrupting T-cell homeostasis: how HIV-1 infection causes disease.

Abstract: In the absence of antiretroviral treatment, HIV-1 establishes a chronic infection that is marked by the progressive depletion of CD4+ T-cells. Of all the viral infections that afflict humans, only HIV-1 is known to cause such profound and inevitable CD4+ T-cell loss. Yet the mechanisms by which this depletion arises remain a matter of controversy. This review will address what is exceptional about HIV-1 infection that sets it apart from other viral infections. Recent attempts to understand HIV-1 pathogenesis have set aside the view that CD4+ T-cell depletion is effected solely by HIV-1-mediated killing in favor of a more complete explanation that also includes T-cell dynamics and, more specifically, chronic immune activation as a central factor in HIV-1 pathogenesis. This review will address the contributions of the virus itself, T-cell activation, T-cell reconstitution, and target cell availability, in the shaping of these dynamics during the disease. The acute and chronic phases of HIV-1 disease will be addressed separately, as they manifest distinctive viral and T-cell dynamics and are the setting for different pathogenic mechanisms. New observations suggest that considerable damage is caused to the immune system during the acute phase of the infection, resulting in a substantial early lymphopenia of the memory CD4+ T-cell pool that may have a profound impact on the subsequent course of the infection. Other observations reveal a strategy in which HIV-1 induces immune activation to generate replaceable targets, activated CD4+ T-cells, which sustain its replication. Although the majority of these target cells are short-lived by physiological design, chronic activation can indirectly strain homeostasis of the naive and resting memory T-cell pools in a number of ways. In the context of virus-induced damage to the lymphoid tissues and cells that maintain these T-cell pools, and physiological limitations in peripheral CD4+ T-cell renewal, this homeostatic strain leads to the progressive depletion of the more vulnerable CD4+ T-cell pools.

Worldwide transmission of drug-resistant HIV.

Abstract: The availability of highly active antiretroviral therapy (HAART), that suppresses replication of the human immunodeficiency virus type 1 (HIV-1), has dramatically improved the prognosis of HIV-infected patients. In populations with access to HAART, the course of the infection has changed from an inevitably fatal disease, characterized by a high incidence of opportunistic infections, into a potentially-treatable chronic condition. Unfortunately, HAART does not durably suppress HIV replication in 20-50% of treatment-naive patients and in up to 50-70% of treatment-experienced patients. In the majority of patients with viral rebound, drug-resistance-related mutations are detected. New infections through transmission of drug-resistant strains to individuals who have never been exposed to therapy are now being increasingly reported, despite all HIV prevention efforts. Moreover, recent reports correlate new infections by drug-resistant virus with suboptimal therapy response, which raises major public health concerns. Despite a large number of publications on the rate of primary resistance, it is very difficult to draw general conclusions. The large variation in methodology and interpretation illustrates the need for systematic approaches. Global surveillance is urgently warranted to monitor the circulating HIV-strains. In addition, follow-up research has to be performed to reveal the impact of drug resistance on future therapy options. This paper reviews current literature to elucidate the mechanisms, implications and magnitude of transmission of drug-resistant HIV-1.

Polymorphism in HIV-1 non-subtype B protease and reverse transcriptase and its potential impact on drug susceptibility and drug resistance evolution.

Abstract: HIV-1 non-subtype B viruses are predominant worldwide At least 9 different HIV-1 group M subtypes and 14 circulating recombinant forms differ from one another by 10-15% in their pol gene, which includes the coding regions for the viral protease and reverse transcriptase (RT), the current targets of antiretroviral drugs Inter-subtype genotypic diversity includes polymorphism at amino acid residues known to be related to drug resistance in HIV-1 subtype B Whether polymorphism alters protease and RT function, drug susceptibility, or clinical response to treatment, is unclear Worldwide dissemination of non-subtype B viruses and increasing availability of antiretroviral drugs in the developing world will expand drug use and the likelihood of drug resistance in non-subtype B viruses In this review we define and characterize inter-subtype RT and protease polymorphism, and examine the evidence for genotypic and phenotypic differences between HIV-1 subtypes as well as the potential for different clinical responses and evolution of drug resistance among non-B infected individuals

Hepatotoxicity of antiretroviral therapy.

Abstract: Hepatotoxicity is a serious complication in patients taking HAART. Coinfection with hepatitis viruses increases the risk of liver toxicity while taking antiretroviral therapy. Baseline transaminases should be checked before beginning antiretorviral therapy and all patients should be screened for pre-existing liver disease, most notably hepatitis B and C infections. Regular monitoring of transaminases is mandatory when commencing antiretroviral therapy. In patients with normal liver function, transaminases may be checked monthly after commencing HAART for the first 3 months. If stable this can be broadened to 3 month intervals. In patients with pre-existing liver disease monitoring should be performed more frequently (every 2 weeks) when initiating therapy. Once stable liver enzymes should be checked monthly. The less hepatotoxic drugs such as lamivudine and abacavir should be preferred in patients at high risk for hepatotoxicity. Risks include co-infection with hepatitis B and C viruses, a previous record of hepatotoxicity, cirrhosis, obesity and female gender. Minor enzyme elevations (< 5-fold upper normal limit) are generally safe to tolerate and usually resolve. Patients must be closely observed with regular liver function tests and a hypersensitivity type drug reaction should be excluded. The onset of clinical symptoms, elevated serum lactate or evidence of severe hepatic dysfunction (coagulopathy or elevation of ammonia levels) are suggestive of severe toxicity and HAART should be withheld. Treatment of suspected HAART related hepatotoxicity should first involve withdrawal of therapy. Hypersensitivity reactions may be treated with corticosteroids. Nucleoside-induced mitochondrial damage may improve with riboflavin or thiamine therapy.

HIV-1 gp41: mediator of fusion and target for inhibition.

Abstract: The bipartite envelope glycoprotein (Env) of the human immunodeficiency virus type 1 (HIV-1) performs two essential functions for initiating virus infection. The gp120 surface subunit of Env binds cell receptors to attach virus to target cells and regulate viral entry. The gp41 transmembrane subunit fuses host-cell and viral membranes to deliver the viral core into the cell cytoplasm. The two subunits derive from a polyprotein precursor, gp160. Cleavage of gp160 in the biosynthetic pathway creates mature Env consisting of the noncovalently-associated gp120/gp41 that is primed for viral entry. While performing distinct operations in HIV entry, the activities of the gp120 and gp41 subunits must be highly coordinated in order to lead to successful infection. This review highlights structure-function relationships in Env, with a focus on the heptad-repeat regions in the ectodomain of gp41. The mechanism of Env-mediated membrane fusion and ways to interfere with this process using inhibitors and antibodies that target gp41 are discussed.

Resistance to HIV-1 infection: lessons learned from studies of highly exposed persistently seronegative (HEPS) individuals.

Abstract: The medical, social, and economic impact of the human immunodeficiency virus (HIV) epidemic has underscored the need to quickly develop effective control strategies Vigorous efforts to develop a vaccine and therapeutic agents have not yet succeeded in containing the spread of the virus Studies of persons who remain uninfected despite extensive exposure to HIV continue to provide valuable information on mechanisms of natural protection, which can then be applied to vaccine design Natural resistance to infection has been studied in multiple high-risk cohorts, with resistance attributed to a combination of innate, genetic, and acquired immune system-mediated mechanisms The relative contributions of these factors to natural resistance to HIV-1 infection and possible ways in which they can be applied to vaccine design are discussed

Forecasting the future of HIV epidemics: the impact of antiretroviral therapies & imperfect vaccines.

Abstract: Mathematical models can be used as health policy tools and predictive tools. Here we review how mathematical models have been used both to predict the consequences of specific epidemic control strategies and to design epidemic control strategies. We review how models have been used to evaluate the potential impact on HIV epidemics of (i) combination antiretroviral therapies (ART) and (ii) imperfect vaccines. In particular, we discuss how models have been used to predict the potential effect of ART on incidence rates, and to predict the evolution of an epidemic of drug-resistant HIV. We also discuss, in detail, how mathematical models have been used to evaluate the potential impact of prophylactic, live-attenuated and therapeutic HIV vaccines. We show how HIV vaccine models can be used to evaluate the epidemic-level impact of vaccine efficacy, waning in vaccine-induced immunity, vaccination coverage level, and changes (increases or decreases) in risky behavior. We also discuss how mathematical models can be used to determine the levels of cross-immunity that vaccines will need to attain if they are to be used to control HIV epidemics in countries where more than one subtype is being transmitted.

The mucosal immune system and HIV-1 infection.

Abstract: Recent progress in HIV-1 and SIV pathogenesis has revealed that mucosal tissues, primarily the gastrointestinal tract, are major sites for early viral replication and CD4+ T-cell destruction, and may be the major viral reservoir, even in patients receiving HAART. This is likely attributable to the fact that the majority of mucosal CD4+ T-cells co-expressing chemokine receptors requited for HIV-1 entry, reside in mucosal tissues. Furthermore, the intestinal mucosal immune system is continuously bombarded by dietary antigens, resulting in continual lymphocyte activation, dissemination, and homing of these activated lymphocytes (including CCR5+CD4+ T-cells) throughout mucosal tissues. Thus, the intestinal immune system represents a very large target for HIV-infection, which is continually generating newly activated CD4+ T-cells that are the preferred target of infection. Thus, HIV-1 appears uniquely adapted to persist and thrive in the mucosal-tissue environment. The selective loss of intestinal CD4+ T-cells from immune-effector sites is also likely to explain, at least in part, the preponderance of opportunistic infections at mucosal sites. It is increasingly evident that effective therapies and vaccines must be directed towards eliminating HIV-1 in mucosal tissue reservoirs, protecting mucosal CD4+ T-cells and stimulating effective mucosal immune responses.

HIV infection and the cardiovascular system

Abstract: Better treatment and supportive care are prolonging the lives of patients with HIV, which is resulting in a higher prevalence of long-term effects of HIV. Autopsy and echocardiography studies support frequent involvement of the heart in advanced stages of HIV infection. The most common cardiac manifestations of HIV are dilated cardiomyopathy, myocarditis, pulmonary hypertension, pericardial effusion, endocarditis, HIV-associated malignant neoplasms, and drug-related cardiotoxicity. Highly active antiretroviral therapy (HAART) has prolonged many patients' lives, but many cardiac sequelae of HIV are not affected by HAART and continue to develop even with treatment. In addition, HAART itself may be associated with an increase in peripheral artery and coronary artery diseases. This review focuses on the most recent knowledge about HIV-associated cardiovascular disease. Careful cardiovascular evaluation in the course of HIV disease can identify cardiac complications early enough to treat. In addition, the study of HIV-related cardiovascular disease may shed light on the mechanisms of non-HIV-related cardiovascular disease.

Reservoirs of HIV-1 in vivo: implications for antiretroviral therapy.

Abstract: The eradication of HIV-1 from infected individuals remains the ultimate goal of all anti-HIV therapeutics Although highly active antiretroviral therapy (HAART) has led to a profound decrease in morbidity and mortality in infected people by suppressing HIV replication, the virus continues to evolve slowly during therapy even when patients achieve below detectable levels of HIV in plasma HIV-1 persists in latently infected memory CD4+ T cells and there is minimal decay of HIV in this compartment despite prolonged HAART Various other reservoirs and sanctuary sites harboring HIV are also established in vivo during antiretroviral therapy Collectively these sites represent a major impediment to the eradication of HIV-1 This review presents a detailed overview of various reservoir sites in vivo, and discusses their impact on the success and failure of HAART for HIV patients In addition, it addresses the effect of sub-optimal drug concentrations on reservoir establishment and outlines future therapeutic strategies to counteract these reservoirs and sanctuaries

Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8): key aspects of epidemiology and pathogenesis.

Abstract: The search for a transmissible infectious agent as the cause of Kaposi's sarcoma lead to the discovery in 1994 of Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus type 8 (HHV8). KSHV is the only human gamma2 herpesvirus (rhadinovirus) known so far, and is also associated with two other AIDS-related lymphoproliferative disorders: primary effusion lymphoma (PEL) and the plasma-cell variant of multicentric Castleman's disease (MCD). This review addresses key aspects of KSHV epidemiology, life cycle and pathogenesis, including the role played by key latent and lytic KSHV genes.

Mechanisms involved in non-progressive HIV disease.

Abstract: HIV disease is a culmination of a complex interplay between both viral and host factors. As the underlying biological and molecular mechanisms involved in determining disease status are not fully understood, the relationship between the two can be better extrapolated using long-term non-progressing individuals who harbor the virus but clinically show some form of immunologic control over it. Only a fraction of individuals comprising less than 1% of the total HIV-infected population show no clinical sign of infection for an extended period of time. Continued immunologic characterization of such non-progressing individuals will lead to the delineation of anti-HIV mechanisms and development of immunotherapeutic modulators for controlling HIV. In this article, we present recent progress made in non-progressive HIV disease, and summarize the vast array of literature on factors and mechanisms which determine the effectiveness of viral and antiviral responses in maintaining a non-progressive state of HIV infection.

Protease inhibition in African subtypes of HIV-1.

Abstract: Of the 42 million people infected with HIV-1 worldwide, 30 million are in Africa. However, the HIV-1 subtypes prevalent in Africa are not the same that are prevalent in North America and Western Europe. In these developed regions, subtype B is responsible for the vast majority of HIV infections, whereas in sub-Saharan Africa subtypes A and C, and to a lesser extent subtype G, account for most of the infections. These subtypes exhibit genomic differences as large as 30% with respect to subtype B. These differences involve current drug targets, including the HIV-1 protease. Since protease inhibitors have been developed and tested against the HIV-1 B subtype, and proteases from other subtypes carry up to ten amino acid polymorphisms, it is important to assess the influence of these naturally occurring polymorphisms on the potency of existing inhibitors, as well as their synergistic interactions with mutations known to cause drug resistance. This review will examine the effects of naturally occurring polymorphisms on the efficacy of current protease inhibitors and the effects of well characterized drug-resistant mutations within the framework of non-B subtypes. At the biochemical level, non-B-subtype polymorphisms lower the binding affinities of existing clinical inhibitors, but not to the point of causing drug resistance. However, these polymorphisms amplify the effects of mutations causing drug resistance and may play a role in the long-term viability of these inhibitors.

Adenoviruses as vectors for HIV vaccines.

Abstract: The tropism of adenoviruses (Ad) for mucosal epithelium makes them ideal vectors for the development of recombinant Ad-HIV vaccines. Currently, several Ad-HIV vaccine candidates are being tested in clinical and preclinical trials. Here, we review the progress on the safety, immunogenicity and efficacy of replication-competent and replication-defective Ad-HIV and Ad-SIV vaccines in animal models, including non-human primates. Replication-defective Ad-SIV gag vaccines have elicited cellular responses that control intravenous infection with an HIV/SIV chimeric immunodeficiency virus (SHIV), while replication-competent Ad-SIV env/rev/gag/nef vaccines have stimulated cellular and humoral responses and protected rhesus monkeys from a mucosal challenge with pathogenic SIV. The composition and advantages of these and other Ad vaccines are described, with particular emphasis on strategies to increase the immunogenicity of the replication-defective vaccines and the safety and efficacy of the replication-competent approach. The overall efficacy of Ad-based vaccines in non-human primates should encourage further evaluation of additional replication-competent and replication-defective Ad-HIV candidates in human trials.

The clades of HIV: their origins and clinical significance.

Abstract: It is over 20 years since the identification of HIV as the causative agent of AIDS. Despite the innovation and perseverance of biomedical researchers, HIV has cumulatively infected over 60 million individuals and caused the deaths of over 28 million, the majority in the developing world. There is perhaps no greater need in medical science than the development of more effective treatments for HIV and, ultimately, a protective vaccine. The spread of an extraordinary range of variants of HIV has implications for diagnosis and therapy. As the availability of antiretrovirals increases, data on the clinical response to treatment for non-B subtype infections has increasing relevance. Efficient targeting of the extreme genetic diversity of HIV-1, and an understanding of the processes underlying this, represents one of the major challenges in the control of this ongoing pandemic.

HIV protease inhibitors and dyslipidemia.

Abstract: Highly active antiretroviral therapy (HAART) significantly prolongs the lives of HIV-infected patients. Current regimens may consist of a protease inhibitor (PI) combined with at least two or more other antiretroviral drugs. PI administration has been shown to be associated with alterations in plasma lipids (i.e. prompt and sustained increases in total cholesterol, low-density lipoprotein cholesterol, and triglycerides) and insulin levels that place PI-treated patients at risk for coronary heart disease (CHD). Because PI-associated dyslipidemia is generally asymptomatic and occurs in patients who are often younger than those traditionally at risk for CHD, the need for primary prevention of acute coronary events in these patients is often unappreciated. Statins form a significant component of pharmacotherapy for PI-associated dyslipidemia. However, because PIs and all statins except pravastatin are metabolized by the cytochrome P450 (CYP) system, co-administration of these agents produces a significant risk of drug interactions and statin-induced hepatotoxicity and myopathy. This risk can be greatly reduced by administering a statin not metabolized by CYP. The need for lipid reduction therapy may be minimized with the use of new PIs that are comparable in efficacy to current PIs but do not negatively affect lipid levels.

Post-entry restriction of retroviral infections.

Abstract: Pathogenic retroviruses have driven the evolution of several dominant-acting mechanisms able to block infection and protect the host. These are exemplified by the mouse gene Fv1, which encodes a Gag-like protein able to protect against murine leukemia virus (MLV) infection. The block is saturable, occurs after reverse transcription and is directed against the viral capsid gene. Several other mammalian species are also able to block MLV infection with the same capsid specificity. A human gene with this activity has been named Ref1. Recently, primates have been shown to restrict a variety of retroviruses only very distantly related to MLVs through a gene named Lv1. Restricted viruses include MLV as well as lentiviruses such as human immunodeficiency viruses 1 and 2, simian immunodeficiency virus and equine infectious anemia virus. In each case the block to one retrovirus can be saturated by co-infection with a second restricted virus. The possible mechanisms of action, and evolutionary consequences of restriction, are reviewed.

AIDS vaccine development: the long and winding road.

Abstract: Development of a vaccine that provides sterilizing immunity against HIV infection remains an elusive goal, due primarily to the difficulty in generating neutralizing antibodies to primary HIV isolates. In lieu of a present solution to this problem, recent approaches to develop vaccines against HIV/AIDS have focused not on preventing infection outright, but on eliciting potent antiviral CD8+ T-cell responses to limit HIV replication in individuals who become infected after vaccination. Successful control of HIV replication in vivo, enabled by vaccine-elicited immune responses should, in turn, attenuate an individual's rate of progression to AIDS while reducing their likelihood of subsequently transmitting HIV. Recent pre-clinical evaluation of CTL-based vaccines in non-human primate models of AIDS has shown several different vaccine modalities (e.g. heterologous 'prime/boost' strategies such as DNA + recombinant viral vectors) to be capable of eliciting high-level cellular immune responses that are associated with limitation of virus replication and protection against disease following challenge with select pathogenic virus isolates. However, it is not currently known to what extent these protective effects, observed under optimal experimental conditions in select animal models, can be translated into relevant protection of humans against AIDS. In this article we discuss the promise, potential limitations, and scientific challenges that currently provide the context for efforts to develop and successfully employ a safe and effective AIDS vaccine.

HIV/AIDS care and treatment in sub-Saharan Africa.

Abstract: Antiretroviral (ARV) drugs have become the cornerstone of care and treatment for AIDS in North America, Brazil, and Europe. Twenty years into the epidemic, and more than 10 years after the introduction of ARV’s, effective global treatment of AIDS, particularly in sub-Saharan Africa where the epidemic is most concentrated, is an extraordinary challenge. Guidelines and experience in anti-microbial prophylaxis, prescription and monitoring of ARV’s in resource-rich countries should inform the efforts to scale-up AIDS care and treatment in Africa. Here, we review the considerable experience of ARV treatment acquired largely in the Americas and Europe, and the fledgling clinical trials and observational studies in Africa. Implementation of safe, effective, and equitable access to ARV’s in Africa should be cognizant of the guidelines for ARV treatment in the Northern countries. Careful observation and operational research to accrue more African data, and evaluate regional and local solutions to this daunting challenge, will identify new approaches to scaling-up of ARV treatment.

Stavudine in the face of cross-resistance between HIV-1 nucleoside reverse transcriptase inhibitors: a review.

Abstract: Despite the current availability of over 15 antiretroviral drugs, diminishing antiretroviral options due to drug cross-resistance constitute a real challenge beyond first-line therapy. Although stavudine (d4T) shares several resistance mutations with other drugs in its class -i.e. nucleoside analogue mutations (NAMs)- literature regarding the actual impact of NAMs on HIV-1 resistance to d4T is conflicting. Several studies conducted over the past few years have, however, shown that the frequency with which d4T selects NAMs is much lower than using zidovudine (AZT), particularly when combined with lamivudine (3TC). In the latter case, NAMs have been found in less than 5% of cases after more than 12 weeks of therapy. In vitro studies have also shown that the impact of d4T on phenotypic drug susceptibility is much lower than that of AZT, with similar genotypic profiles. Few clinical trials have attempted to define a clinically relevant cut-off for phenotypic resistance to d4T. The results of these trials differ considerably and are highly dependent on the studied population. Nonetheless, these data help to clarify the strategic use of d4T in antiretroviral therapy, and to determine the best sequencing options for nucleoside reverse transcriptase inhibitors.

Saquinavir/low-dose ritonavir: its use in HIV infection.

Abstract: Exposure to saquinavir can be increased considerably by pharmacokinetic enhancement with ritonavir, without having a substantial impact on tolerability. Clinical trials indicate that both once-daily and twice-daily saquinavir/ritonavir treatment regimens, generally at dosages of 1,600 mg/100 mg once daily and 1,000 mg/100 mg twice daily, provide potent and sustained viral suppression and are well tolerated. In addition, data suggest that "double-boosting" strategies, including the combination of saquinavir with lopinavir/ritonavir, provide valuable treatment options in the salvage setting.