Differential escape patterns within the dominant HLA-B*57:03-restricted HIV Gag epitope reflect distinct clade-specific functional constraints.

UNLABELLED: HLA-B*57:01 and HLA-B*57:03, the most prevalent HLA-B*57 subtypes in Caucasian and African populations, respectively, are the HLA alleles most protective against HIV disease progression. Understanding the mechanisms underlying this immune control is of critical importance, yet they remain unclear. Unexplained differences are observed in the impact of the dominant cytotoxic T lymphocyte (CTL) response restricted by HLA-B*57:01 and HLA-B*57:03 in chronic infection on the Gag epitope KAFSPEVIPMF (KF11; Gag 162 to 172). We previously showed that the HLA-B*57:03-KF11 response is associated with a >1-log-lower viral setpoint in C clade virus infection and that this response selects escape mutants within the epitope. We first examined the relationship of KF11 responses in B clade virus-infected subjects with HLA-B*57:01 to immune control and observed that a detectable KF11 response was associated with a >1-log-higher viral load (P = 0.02). No evidence of HLA-B*57:01-KF11-associated selection pressure was identified in previous comprehensive analyses of >1,800 B clade virus-infected subjects. We then studied a B clade virus-infected cohort in Barbados, where HLA-B*57:03 is highly prevalent. In contrast to findings for B clade virus-infected subjects expressing HLA-B*57:01, we observed strong selection pressure driven by the HLA-B*57:03-KF11 response for the escape mutation S173T. This mutation reduces recognition of virus-infected cells by HLA-B*57:03-KF11 CTLs and is associated with a >1-log increase in viral load in HLA-B*57:03-positive subjects (P = 0.009). We demonstrate functional constraints imposed by HIV clade relating to the residue at Gag 173 that explain the differential clade-specific escape patterns in HLA-B*57:03 subjects. Further studies are needed to evaluate the role of the KF11 response in HLA-B*57:01-associated HIV disease protection. IMPORTANCE: HLA-B*57 is the HLA class I molecule that affords the greatest protection against disease progression in HIV infection. Understanding the key mechanism(s) underlying immunosuppression of HIV is of importance in guiding therapeutic and vaccine-related approaches to improve the levels of HIV control occurring in nature. Numerous mechanisms have been proposed to explain the HLA associations with differential HIV disease outcome, but no consensus exists. These studies focus on two subtypes of HLA-B*57 prevalent in Caucasian and African populations, HLA-B*57:01 and HLA-B*57:03, respectively. These alleles appear equally protective against HIV disease progression. The CTL epitopes presented are in many cases identical, and the dominant response in chronic infection in each case is to the Gag epitope KF11. However, there the similarity ends. This study sought to better understand the reasons for these differences and what they teach us about which immune responses contribute to immune control of HIV infection.

Clinical and demographic factors associated with low viral load in early untreated HIV infection in the INSIGHT Strategic Timing of AntiRetroviral Treatment (START) trial.

OBJECTIVES: A small subset of HIV-positive adults have low HIV RNA in the absence of therapy, sometimes for years. Clinical factors associated with low HIV RNA in early infection have not been well defined. METHODS: We assessed factors associated with low plasma HIV RNA level at study entry in the Strategic Timing of AntiRetroviral Treatment (START) trial. All START participants had a baseline HIV RNA assessment within 60 days prior to randomization. The key covariables considered for this analysis were race, and hepatitis B virus (HBV) and hepatitis C virus (HCV) status. We assessed factors associated with HIV RNA ≤ 50 and ≤ 400 HIV-1 RNA copies/mL using logistic regression. Because of the strong association between region of randomization and baseline low HIV RNA, analyses were stratified by region. RESULTS: We found that, of 4676 eligible participants randomized in START with a baseline HIV RNA assessment, 113 (2.4%) had HIV RNA ≤ 50 copies/mL at baseline, and a further 257 (5.5%) between 51 and 400 copies/mL. We found that HIV exposure routes other than male homosexual contact, higher high-density lipoprotein (HDL) cholesterol levels, higher CD4 cell counts, and higher CD4:CD8 ratio were associated with increased odds of low HIV RNA. HCV antibody positivity was borderline statistically significantly associated with low HIV RNA. Race and HBV surface antigen positivity were not significantly associated with low HIV RNA. CONCLUSIONS: In a modern cohort of individuals with early untreated HIV infection, we found that HIV exposure routes other than male homosexual contact and higher HDL cholesterol were associated with increased odds of low HIV RNA.

Reduction of HIV persistence following transplantation in HIV-infected kidney transplant recipients.

Chronic inflammation may contribute to human immunodeficiency virus (HIV) persistence through a number of potential pathways. We explored the impact of immunosuppressant therapy on peripheral blood measures of HIV persistence following kidney transplantation. Stored plasma and peripheral blood mononuclear cells prior to transplantation and at weeks 12, 26, 52 and 104 posttransplant were obtained from 91 transplant recipients. In a multivariate model, higher pretransplant plasma HIV RNA level (p < 0.0001) and a longer duration of follow-up posttransplant (p = 0.09) were associated with higher posttransplant plasma HIV RNA levels. A higher baseline HIV DNA (p < 0.0001) was significantly associated with higher HIV DNA levels posttransplant, while higher CD4+ T cell count (p = 0.001), sirolimus use (p = 0.04) and a longer duration of follow-up (p = 0.06) were associated with lower posttransplant HIV DNA levels. The association between sirolimus exposure and lower frequency of cells containing HIV DNA levels posttransplant suggest that the immune-modifying drugs may affect the level of HIV persistence during effect therapy. Future studies of sirolimus as a reservoir-modifying agent are warranted.

Variations in the heme oxygenase-1 microsatellite polymorphism are associated with plasma CD14 and viral load in HIV-infected African-Americans.

Heme oxygenase-1 (HO-1) is an anti-inflammatory enzyme that maintains homeostasis during cellular stress. Given previous findings that shorter length variants of a HO-1 promoter region GT(n) microsatellite polymorphism are associated with increased HO-1 expression in cell lines, we hypothesized that shorter variants would also be associated with increased levels of HO-1 expression, less inflammation and lower levels of inflammation-associated viral replication in human immunodeficiency virus (HIV)-infected subjects. Healthy donors (n = 20) with shorter GT(n) repeats had higher HO-1 mRNA transcript in peripheral blood mononuclear cells stimulated with lipopolysaccharide (r = -0.38, P = 0.05). The presence of fewer GT(n) repeats in subjects with untreated HIV disease was associated with higher HO-1 mRNA levels in peripheral blood (r = -0.41, P = 0.02); similar observations were made in CD14(+) monocytes from antiretroviral-treated subjects (r = -0.36, P = 0.04). In African-Americans, but not Caucasians, greater GT(n) repeats were correlated with higher soluble CD14 levels during highly active antiretroviral therapy (r = 0.38, P = 0.007) as well as higher mean viral load off-therapy (r = 0.24, P = 0.04). These data demonstrate that the HO-1 GT(n) microsatellite polymorphism is associated with higher levels of HO-1 expression and that this pathway may have important effects on the association between inflammation and HIV replication.

Lenalidomide enhancement of human T cell functions in human immunodeficiency virus (HIV)-infected and HIV-negative CD4 T lymphocytopenic patients.

Suppressed T cell functions in human immunodeficiency virus (HIV) infection were identified and corrected by lenalidomide in middle-aged HIV-infected patients. Chemotaxis of T cells from HIV-infected men (n = 6, mean 43 years) to sphingosine 1-phosphate (S1P) and CCL21 was significantly lower than that of HIV-negative men (n = 6, mean 41 years), and was enhanced significantly up to control levels by 100 and 1000 nM lenalidomide. Generation of interleukin (IL)-2, but not interferon (IFN)-γ, by T cells of middle-aged HIV-infected men was significantly lower than that for controls and was increased significantly by 10-1000 nM lenalidomide up to a maximum of more than 300%. CD4 and CD8 T cells isolated from healthy middle-aged men and reconstituted in vitro at a low CD4 : CD8 ratio typical of HIV infection had depressed chemotaxis to S1P, but not CCL21, and generation of IL-2, but not IFN-γ. Significant enhancement of chemotaxis to S1P and CCL21 was induced by 100-1000 nM lenalidomide only for normal T cells at a low CD4 : CD8 ratio. T cells from HIV-negative middle-aged CD4 T lymphocytopenic patients (n = 3), with a CD4 : CD8 ratio as low as that of HIV-infected patients, had similarly diminished chemotaxis to S1P and CCL21, and depressed generation of IL-2, but not IFN-γ. Lenalidomide at 30-1000 nM significantly enhanced chemotaxis to S1P and IL-2 generation for T cells from HIV-negative CD4 T lymphocytopenic patients as from HIV-infected patients, with less effect on CCL21-elicited chemotaxis and none for IFN-γ generation. Defects in functions of T cells from middle-aged HIV-infected men are partially attributable to CD4 T lymphocytopenia and are corrected by lenalidomide.

Increased production of IL-7 accompanies HIV-1-mediated T-cell depletion: implications for T-cell homeostasis.

We hypothesized that HIV-1-mediated T-cell loss might induce the production of factors that are capable of stimulating lymphocyte development and expansion. Here we perform cross-sectional (n = 168) and longitudinal (n = 11) analyses showing that increased circulating levels of interleukin (IL)-7 are strongly associated with CD4+ T lymphopenia in HIV-1 disease. Using immunohistochemistry with quantitative image analysis, we demonstrate that IL-7 is produced by dendritic-like cells within peripheral lymphoid tissues and that IL-7 production by these cells is greatly increased in lymphocyte-depleted tissues. We propose that IL-7 production increases as part of a homeostatic response to T-cell depletion.

Impaired replication of protease inhibitor-resistant HIV-1 in human thymus.

Many HIV-1-infected patients treated with protease inhibitors (PI) develop PI-resistant HIV-1 variants and rebounds in viremia, but their CD4+ T-cell counts often do not fall. We hypothesized that in these patients, T-cell counts remain elevated because PI-resistant virus spares intrathymic T-cell production. To test this, we studied recombinant HIV-1 clones containing wild-type or PI-resistant protease domains, as well as uncloned isolates from patients, in activated peripheral blood mononuclear cells, human thymic organ cultures and human thymus implants in SCID-hu Thy/Liv mice. In most cases, wild-type and PI-resistant HIV-1 isolates replicated to similar degrees in peripheral blood mononuclear cells. However, the replication of PI-resistant but not wild-type HIV-1 isolates was highly impaired in thymocytes. In addition, patients who had PI-resistant HIV-1 had abundant thymus tissue as assessed by computed tomography. We propose that the inability of PI-resistant HIV-1 to replicate efficiently in thymus contributes to the preservation of CD4+ T-cell counts in patients showing virologic rebound on PI therapy.

Protease inhibitors as immunomodulatory drugs for HIV infection.

More than 20 drugs from four therapeutic drug classes are widely available for the management of human immunodeficiency virus (HIV) infection, with promising drugs from two new drug classes expected to be approved by the US Food and Drug Administration (FDA) in mid-to-late 2007 (Table 1). When used in combination, these drugs can lead to durable and perhaps indefinite suppression of viral replication.

Predominance of weakly cytotoxic, T-betLowEomesNeg CD8+ T-cells in human gastrointestinal mucosa: implications for HIV infection.

The gastrointestinal mucosa is an important site of HIV acquisition, viral replication, and pathogenesis. Immune cells in mucosal tissues frequently differ in phenotype and function from their non-mucosal counterparts. Although perforin-mediated cytotoxicity as measured in blood is a recognized correlate of HIV immune control, its role in gastrointestinal tissues is unknown. We sought to elucidate the cytotoxic features of rectal mucosal CD8+ T-cells in HIV infected and uninfected subjects. Perforin expression and lytic capacity were significantly reduced in rectal CD8+ T-cells compared with their blood counterparts, regardless of HIV clinical status; granzyme B (GrzB) was reduced to a lesser extent. Mucosal perforin and GrzB expression were higher in participants not on antiretroviral therapy compared with those on therapy and controls. Reduction in perforin and GrzB was not explained by differences in memory/effector subsets. Expression of T-bet and Eomesodermin was significantly lower in gut CD8+ T-cells compared with blood, and in vitro neutralization of TGF-ß partially restored perforin expression in gut CD8+ T-cells. These findings suggest that rectal CD8+ T-cells are primarily non-cytotoxic, and phenotypically shaped by the tissue microenvironment. Further elucidation of rectal immune responses to HIV will inform the development of vaccines and immunotherapies targeted to mucosal tissues.

Activity of a ritonavir plus saquinavir-containing regimen in patients with virologic evidence of indinavir or ritonavir failure.

OBJECTIVE: To evaluate the virologic activity of a ritonavir plus saquinavir-containing regimen in patients who have failed an indinavir or ritonavir-containing regimen. DESIGN: Patients were identified through a retrospective study evaluating the incidence of indinavir or ritonavir failure in our clinic. PATIENTS: Eighteen patients failing indinavir or ritonavir therapy and who switched to a ritonavir-saquinavir-containing regimen were evaluated. Indinavir or ritonavir failure was defined as a plasma viral load > 1500 copies/ml (branched DNA) after 16 weeks of continuous therapy. INTERVENTIONS: All patients switched to ritonavir (400 mg twice daily) plus saquinavir (400 mg twice daily) and received concurrent therapy with two nucleoside reverse transcriptase inhibitors (NRTI). Twelve of the 18 patients modified their NRTI regimen at the time ritonavir-saquinavir was initiated. OUTCOME MEASURES: Plasma viral load was monitored using a branched DNA assay. Genotypic analysis was performed using a point mutation differential hybridization technique, and was confirmed with direct sequencing. RESULTS: Fourteen out of 18 patients completed at least 24 weeks of therapy; the remaining four patients discontinued therapy after week 12 due to a lack of virologic response or intolerance. Plasma viral load decreased a median 1.4 log10 after 4 weeks of treatment with ritonavir-saquinavir. Only four patients had a greater than 0.5 log10 decrease in viral load after 24 weeks of therapy. In eight out of 10 patients evaluated, the V82A mutation was present at the time of the switch to ritonavir-saquinavir. Viral rebound on ritonavir-saquinavir was associated with the emergence of mutations at amino acids 46, 48, 54 and 90. CONCLUSION: The combination of ritonavir, saquinavir and two NRTI resulted in a moderate but transient suppression of viral replication in patients who have failed indinavir or ritonavir therapy. Failure of ritonavir-saquinavir may be associated with the emergence of mutations associated with resistance to ritonavir/saquinavir monotherapy, particularly the L90M mutation.

Loss of antiretroviral drug susceptibility at low viral load during early virological failure in treatment-experienced patients.

BACKGROUND: Clinical studies have demonstrated a correlation between the response to second-line antiretroviral therapy and the number of drugs in the regimen to which the virus is susceptible. These studies have largely been performed in patients with viral loads over 1000 copies/ml. OBJECTIVES: To examine the evolution of resistance during early virological failure, and the potential role of susceptibility testing in patients with low viral loads (below 1000 copies/ml), in treatment-experienced patients. METHODS: Drug susceptibility and genotypes of HIV-1 from indinavir-experienced patients undergoing therapy with nelfinavir, saquinavir, abacavir and either a second nucleoside reverse transcriptase inhibitor (NRTI) or nevirapine were determined. RESULTS: Sixteen subjects were studied. Five of the ten subjects treated with nevirapine, and one of six treated with a second NRTI, achieved and maintained plasma HIV RNA < 500 copies/ml. Virus from the treatment failures lost susceptibility to one or more treatment drugs, including nelfinavir and/or saquinavir, after 4 to 36 weeks of treatment. In six of the ten failures, virus with new reductions in drug susceptibility was detected prior to failure. In five of the six failures who had at least one plasma sample with a viral load between 50 and 1000 copies/ml, reductions in susceptibility to one or more treatment drugs were detected (viral load range: 260 to 630 copies/ml). CONCLUSIONS: Drug resistance can be detected at viral loads below 1000 copies/ml which may be predictive of treatment failure. Failure of a second line regimen was typically associated with early evolution of resistance in HIV protease.

HIV RNA and CD4 cell count response to protease inhibitor therapy in an urban AIDS clinic: response to both initial and salvage therapy.

OBJECTIVE: To determine the HIV RNA and CD4 cell response to both initial and salvage therapy with protease inhibitor-based therapy, and to examine the relationship between the virological response and pre-therapy characteristics. DESIGN: Observational cohort. SETTING: University-based public hospital AIDS clinic. PATIENTS: HIV-infected adults who received at least 16 continuous weeks' therapy with a potent protease inhibitor (indinavir, ritonavir or nelfinavir)-based regimen, and who have had at least 48 weeks of follow-up. MAIN OUTCOME MEASURES: Plasma HIV RNA and CD4 cell count response at week 48 of therapy for patients receiving their first protease inhibitor-containing regimen, and at week 24 of therapy with a salvage regimen. RESULTS: Of the 337 patients analysed, 170 (50.2%) had a successful outcome (HIV RNA <500 copies/ml after 48 weeks of treatment). Independent predictors of virological failure were higher baseline HIV RNA level, lower baseline CD4 cell count and failure to initiate at least one new nucleoside analog simultaneously at the time protease inhibitor therapy was initiated. The risk of failure increased incrementally across most HIV RNA and CD4 cell strata, with significant increases as the HIV RNA increased above 4.5 log10 copies/ml and the CD4 cell count fell below 100 cells/mm3 (P< or =0.01). The CD4 cell count remained above baseline to week 48 in most patients, regardless of the HIV RNA response. Of the 99 patients who experienced virological failure and switched to a salvage regimen, only 22 (22%) achieved an undetectable HIV RNA level 24 weeks after initiating salvage therapy. Independent predictors of failure with salvage therapy included an HIV RNA greater than 4.0 log10 RNA copies/ml at the time of the switch and failure to use a non-nucleoside reverse transcriptase inhibitor (NNRTI) in the salvage regimen. CONCLUSION: Failure of potent protease inhibitor therapy to suppress HIV RNA levels below detectable levels is common in clinical practice, and can often be explained by their suboptimal use. CD4 T cell counts remain above baseline for at least one year in most patients experiencing virological failure. Successful salvage therapy, which was uncommon, was associated with a low plasma HIV RNA at the time of the switch and the use of a new class of antiretroviral agents (NNRTI) in the salvage regimen.

Protease inhibitor-resistant HIV-1 from patients with preserved CD4 cell counts is cytopathic in activated CD4 T lymphocytes.

OBJECTIVE: To evaluate CD4 T-cell cytopathicity of protease inhibitor (PI)-resistant isolates from patients with preserved CD4 cell counts after long-term virologic failure. METHODS: PI-resistant primary isolates from 14 patients with stable or increasing CD4 T-cell counts despite long-term virologic failure during continuous combination therapy were examined. Replication and cytopathicity were assessed in activated peripheral blood mononuclear cell cultures in the presence and absence of PI using titered stocks of primary HIV-1 isolates and during initial viral isolation. Also studied were PI-sensitive isolates from four of these patients after therapy discontinuation and reversion to PI-sensitive virus and from seven antiretroviral drug-naive patients. Coreceptor use, syncytia-inducing (SI) phenotype and protease sequences were determined by standard methods. RESULTS: All isolates obtained during continued therapy showed genetic markers of PI resistance and decreased phenotypic susceptibility. PI-resistant SI isolates were highly to moderately cytopathic whereas non-syncytia-inducing isolates were moderately to weakly cytopathic. PI-susceptible and PI-resistant isolates obtained after discontinuation of therapy were equally cytopathic at similar replication levels. The cytopathicity of PI-resistant isolates was not altered by PI and was similar to that of isolates from untreated subjects. CONCLUSIONS: Primary isolates from patients showing virologic rebound without net CD4 T-cell loss during continued therapy are as cytopathic as PI-sensitive isolates with equivalent input infectious titer. As with PI-sensitive isolates, cytopathicity of PI-resistant viruses was determined primarily by coreceptor preference. These results suggest that the sustained immunologic response observed after failure of PI-containing regimens is not due to the emergence of PI-resistant strains that are intrinsically less cytopathic for activated peripheral CD4 lymphocytes.

Cerebrospinal fluid response to structured treatment interruption after virological failure.

OBJECTIVE: Structured antiretroviral treatment interruption (STI) has been advocated as a therapeutic strategy for HIV-1 infection. We report initial observations of cerebrospinal fluid (CSF) HIV-1 infection in five patients undergoing serial lumbar punctures (LPs) during STI undertaken following virological failure. DESIGN AND METHODS: In this prospective observational study we quantified HIV-1 RNA concentrations and assessed both phenotypic drug susceptibility profiles and genotypic antiviral drug resistance mutations in CSF and plasma during the period of treatment interruption. CSF white blood cells were also counted, and patients' neurological status monitored. RESULTS: In four of the patients, CSF HIV-1 concentration increased more rapidly than that of the plasma, with consequent reduction in the ratio between plasma and CSF viral loads (pVL : cVL). Three individuals developed robust, though asymptomatic CSF lymphocytic pleocytosis. In all patients the predominant HIV-1 quasispecies shifted simultaneously in CSF and plasma from a drug-resistant to a more drug-susceptible phenotype with identical and simultaneous changes in genotypes associated with drug resistance. CONCLUSIONS: STI may be accompanied by previously unrecognized changes in tissue viral exposures and lymphocyte traffic. Hence, despite 'virological failure' as evidenced by persistent plasma viremia, ongoing antiretroviral treatment prior to its interruption appeared to suppress CSF HIV-1 infection (indeed more effectively than that of plasma) and restrain lymphocyte traffic into the CSF. Simultaneous change of resistance mutations in CSF and plasma was likely due to re-emergence and overgrowth of pre-existing strains with ready exchange of virus between these two compartments, either facilitated by or provoking a local CSF lymphocytosis.

Sustained CD4 responses after virological failure of protease inhibitor-containing therapy.

This article explores current controversies related to 'discordant' responses to antiviral therapy, that is to say, patients with a sustained CD4 cell response despite virological failure. Observational clinical data of patients receiving protease inhibitor-based therapy who had a sustained CD4 cell count even with incomplete viral suppression will be presented, as well as possible mechanisms and clinical implications.

Primary and recombinant HIV type 1 strains resistant to protease inhibitors are pathogenic in mature human lymphoid tissues.

Preserved peripheral CD4+ T cell counts despite virologic failure in patients undergoing protease inhibitor (PI)-containing antiviral regimens are a frequent occurrence in human immunodeficiency virus (HIV) disease. One hypothesis to explain the relative sparing of CD4+ T cells is that HIV strains exhibiting PI resistance concomitantly are attenuated in terms of cytopathicity for mature T cells. To test this hypothesis, we used a three-dimensional human tonsil histoculture microenvironment to assess the pathogenic potential of a panel of primary and recombinant HIV-1 strains derived from patients experiencing PI failure. All the viruses tested replicated efficiently in these cultures and, in some cases, better than comparable wild-type viral isolates. Furthermore, the PI-resistant strains depleted CD4+ T cells potently and comparably with wild-type isolates in these ex vivo lymphoid tissues. These results demonstrate that PI-resistant viruses are not inherently less pathogenic for mature T cells. Therefore, the sustained peripheral lymphocyte counts in patients with selective virologic failure may be due to specific defects in viral replication in other cell compartments or to an undefined host adaptation to viral infection during PI therapy.

Failure of HIV-1 protease inhibitors to fully suppress viral replication. Implications for salvage therapy.

When used as initial therapy in combination with two nucleoside reverse transcriptase inhibitors, indinavir, ritonavir, nelfinavir and possible saquinavir-soft gel capsule (saquinavir-sgc) are highly effective agents. Patients who have been extensively pretreated, have advanced immunodeficiency or are unable to adhere with therapy are at high risk of failing protease inhibitor therapy. Although relevant prospective, randomized controlled clinical trails have not been reported, failure of a first protease inhibitor appears to compromise future therapeutic options. After resistance to indinavir or ritonavir emerges, salvage therapy with a protease inhibitor-containing regimen may be difficult. Preliminary data indicate that salvage therapy after resistance to saquinavir or nelfinavir emerges may be possible; however, this requires further investigation. The activity of newer agents, such as amprenavir or ABT 378, in salvage regimens is unknown. Until these issues are addressed in large prospective studies, clinicians should assume that cross-resistance will be common among all protease inhibitors.

Antiretroviral agents: the next generation.

AIDS: Four new drugs have been developed to overcome the limitations of the currently available anti-HIV drugs, including inconvenient schedules, side effects, and drug interactions. It is hoped that abacavir, efavirenz, adefovir dipivoxil, and amprenavir will be widely available in the near future. Abacavir, a nucleoside reverse transcriptase inhibitor with a twice-daily schedule, offers good bioavailability and generally mild side effects. Efavirenz, a non-nucleoside reverse transcriptase inhibitor with a once daily schedule, may produce side effects such as rash and dizziness. Adefovir dipivoxil, a nucleotide analog with once daily dosing, can cause carnitine depletion and carnitine supplementation is recommended. Amprenavir, a protease inhibitor with twice-daily dosing, has rather mild side effects. Information on efficacy, availability, and resistance for each of these drugs is given.^ieng

Should we argue with success?

AIDS: A case study is presented of a man who was diagnosed with HIV several years ago, and who has been responding well to a d4T/3TC regimen. Dr. Steven Deeks and Dr. Paul Sax both describe possible treatment options and present their opinions of the different options. Both conclude that if the patient is doing well on the current dual nucleoside analogue regimen, it may be best to continue with that treatment, even if it is not the current recommended therapy.^ieng