Multidrug-resistant HIV-1 Infection Research Articles

Multidrug resistance: a clinical approach

New antiretroviral agents have recently become available within existing and new drug classes, increasing treatment options for patients with multidrug-resistant virus. This review discusses the challenges that these new agents pose for the management of treatment-experienced patients. Recent studies of the efficacy and safety of new antiretroviral drugs illustrate that drug regimens containing new agents are well tolerated and can suppress viremia in even the most drug-resistant patients. The goal of any new regimen should therefore be suppression of plasma HIV RNA levels to less than 50 copies/ml, even in treatment-experienced patients. Patients should be given a regimen with at least two, or preferably three, fully active drugs after careful consideration of their treatment and adherence history, current and prior genotype tests, comorbidities, and concomitant medications. Newer and more tolerable agents also offer the possibility of regimen simplification among patients with multidrug-resistant HIV who are virologically suppressed. Clinicians must optimize the pairing and sequencing of recently available antiretroviral agents. Future studies should continue to investigate the optimal use of new agents in order to further improve long-term treatment efficacy in patients with multidrug-resistant HIV infection.

Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial

Use of raltegravir with optimum background therapy is effective and well tolerated in treatment-experienced patients with multidrug-resistant HIV-1 infection. We compared the safety and efficacy of raltegravir with efavirenz as part of combination antiretroviral therapy for treatment-naive patients. Patients from 67 study centres on five continents were enrolled between Sept 14, 2006, and June 5, 2008. Eligible patients were infected with HIV-1, had viral RNA (vRNA) concentration of more than 5000 copies per mL, and no baseline resistance to efavirenz, tenofovir, or emtricitabine. Patients were randomly allocated by interactive voice response system in a 1:1 ratio (double-blind) to receive 400 mg oral raltegravir twice daily or 600 mg oral efavirenz once daily, in combination with tenofovir and emtricitabine. The primary efficacy endpoint was achievement of a vRNA concentration of less than 50 copies per mL at week 48. The primary analysis was per protocol. The margin of non-inferiority was 12%. This study is registered with ClinicalTrials.gov, number NCT00369941. 566 patients were enrolled and randomly allocated to treatment, of whom 281 received raltegravir, 282 received efavirenz, and three were never treated. At baseline, 297 (53%) patients had more than 100 000 vRNA copies per mL and 267 (47%) had CD4 counts of 200 cells per microL or less. The main analysis (with non-completion counted as failure) showed that 86.1% (n=241 patients) of the raltegravir group and 81.9% (n=230) of the efavirenz group achieved the primary endpoint (difference 4.2%, 95% CI -1.9 to 10.3). The time to achieve such viral suppression was shorter for patients on raltegravir than on efavirenz (log-rank test p<0.0001). Significantly fewer drug-related clinical adverse events occurred in patients on raltegravir (n=124 [44.1%]) than those on efavirenz (n=217 [77.0%]; difference -32.8%, 95% CI -40.2 to -25.0, p<0.0001). Serious drug-related clinical adverse events occurred in less than 2% of patients in each drug group. Raltegravir-based combination treatment had rapid and potent antiretroviral activity, which was non-inferior to that of efavirenz at week 48. Raltegravir is a well tolerated alternative to efavirenz as part of a combination regimen against HIV-1 in treatment-naive patients. Merck.

Emerging Pharmacology: Inhibitors of Human Immunodeficiency Virus Integration

The first integrase inhibitor licensed to treat HIV-1 infection was approved in late 2007, more than a decade after the introduction of the first inhibitors of the HIV-1 reverse transcriptase and protease. The unique biochemical and molecular mechanism of action of this novel class of antiretroviral drugs is the fundamental basis for their activity in treating multidrug-resistant HIV-1 infection and is important for understanding both the cellular and in vivo pharmacology and metabolism of these agents. In addition, available pharmacokinetic and drug interaction data for raltegravir and elvitegravir, the two integrase inhibitors that are the most advanced in clinical development to date, are reviewed.

In Vitro Characterization of Multidrug-Resistant HIV-1 Isolates From a Recently Infected Patient Associated With Dual Tropism and Rapid Disease Progression

Multidrug-resistant (MDR) HIV-1 variants are thought to be less fit than wild-type virus. In 2005, we reported a case of transmitted MDR HIV-1 infection associated with dual tropism and rapid clinical progression. Here we report the in vitro characterization of the virus isolates. Replication characteristics of bulk and clonal isolates from this case (MDR-1) were examined and compared with these of a panel of transmitted MDR and wild-type (WT) viruses (MDR-2 approximately 4, WT-1, 2). Infectivity and frequency of infectious virion of propagated isolates were high in MDR-1 biological clones (mean titer, 3.5 x 10(5) TCID50/mL; mean frequency of infectious virion, 1/2444) and its bulk isolate (3.2 x 10(6) TCID50/mL; 1/301) as compared with the other biological clones (7.3 x 10(3) TCID50/mL; 1/21,320). Upslope (log10 p24/mL/d) of viral replication in peripheral blood mononuclear cell culture was much higher in MDR-1 clones (1.30 +/- 0.30: mean +/- SD) than those of MDR-2 approximately 4 (0.75 +/- 0.08) or WT-1, WT-2 clones (0.82 +/- 0.03). The bulk isolate and dual-tropic biological clones from MDR-1 depleted CD4+ T cells very rapidly in vitro compared with the other viruses tested. These findings support the hypothesis that MDR HIV-1 can effectively evolve and compensate not only to retain high-level replication but also to exhibit virulence associated with rapid disease progression.

A Multidrug-Resistant (MDR) HIV Type 1 Infection in a Homosexual Man and Identified Source Patient

We report a case (IC) of multidrug-resistant (MDR) HIV-1 infection in which the identification of the source patient (S) was supported by phylogenetic analysis of the pol gene and by the similarity of env sequences. HIV isolates from IC and S were characterized as non-syncytium viruses: a X4 variant (R(11) E(26)) was identified in both cases according to the V3 loop sequence. The pol mutational profile of IC included multiple protease and reverse-transcriptase inhibitor mutations similar to those in S. The lamivudine/tenofovir/tipranavir/ritonavir/enfuvirtide association was effective for IC but not for S.

Lessons Learned From 2 Patients With Multidrug-Resistant HIV-1 Infection Successfully Treated With a Darunavir-Containing Antiretroviral Treatment Regimen

The authors describe 2 patients with life-threatening multidrug-resistant HIV-1 infection who responded very well to a treatment regimen containing darunavir and enfuvirtide. They discuss the availability of several new treatment options such as darunavir, etravirine, integrase, and CCR5 inhibitors for patients with multidrug-resistant viruses.

Drug Development Strategies for Salvage Therapy: Conflicts and Solutions

WIDESPREAD USE OF ANTIRETROVIRAL DRUGS has led to an increasing prevalence of multidrug-resistant HIV-1 infection, and development of effective treatments for patients with such infections should be a public health priority.1 As recent registrational studies demonstrate, there are often perceived conflicts between the goals of drug development (determining the safety and efficacy of a new drug) and those of clinical practice (providing the most rapid possible access to effective drug combinations). We focus much of our discussion on these studies, as pharmaceutical companies drive much of the current research agenda and can largely specify how they would like their agents to be tested. Conflicts may be reduced, though not entirely eliminated, when studies are sponsored by disinterested third parties. Conflicts between the needs of study participants and the goals of drug development are particularly noteworthy in settings where resistance to one or more drugs in a multidrug regimen can occur. To address the apparent conflicts between the needs of study participants and pharmaceutical manufacturers, we propose changes in current research strategies, summarized as follows. (1) Salvage studies should be designed to minimize the chance that the study participants receive only one active drug. New drugs must be developed in conjunction with other new or existing drugs to create potent regimens; relevant information about how best to combine drugs should be developed early in phase II investigations. (2) Study participants should be maintained on assigned regimens long enough to provide reliable comparisons of toxicity between the new and standard treatments. When crossover to the new regimen is allowed, appropriate methods must be used to adjust for the resulting informative censoring as well as for uncontrolled use of potent drugs. (3) The primary endpoint in salvage studies of antiviral drugs should generally be suppression of virus below levels of detection. (4) Because drug efficacy depends on the genotype of the microbe or cell, studies must provide adequate information for classifying future patients according to their predicted response to therapy. (5) The regulatory policy must be modified to ensure proper review of drugs that are targeted to patients according to genotype of the infecting agents.

Interaction Between Atazanavir and Fosamprenavir in the Treatment of HIV-Infected Patients

Interaction Between Atazanavir and Fosamprenavir in the Treatment of HIV-Infected Patients

Tipranavir.

Tipranavir is a potent and selective non-peptidic HIV-1 protease inhibitor with a markedly improved resistance profile compared with traditional, peptidomimetic protease inhibitors. The presence of five or fewer protease gene mutations or one or two protease inhibitor resistance-associated mutations (PRAMs) is associated with reduced susceptibility to currently available protease inhibitors. However, 16-20 mutations (including three or more PRAMs) may be needed to confer resistance to tipranavir. Tipranavir-based therapy achieved sustained viral suppression for more than 48 weeks in a small phase II trial in multiple protease inhibitor-experienced HIV-infected patients. A large dose-finding study demonstrated potent virological reduction through 14 days of functional monotherapy in heavily pretreated HIV-infected patients with 6 to >20 protease gene mutations at baseline. Two large, ongoing, phase III trials in patients with multi-drug resistant HIV infection are comparing the efficacy of tipranavir/ritonavir 500/200mg twice daily plus a patient-individualised background antiretroviral regimen versus other ritonavir-boosted protease inhibitor regimens. In general, tipranavir has been well tolerated in clinical trials. As with other protease inhibitors, the most common adverse events with tipranavir have been gastrointestinal disturbances.

A Pilot Study of the Use of Mycophenolate Mofetil as a Component of Therapy for Multidrug-Resistant HIV-1 Infection

Log in or Register Subscribe to journalSubscribe Get new issue alertsGet alerts Enter your Email address: Wolters Kluwer Health may email you for journal alerts and information, but is committed to maintaining your privacy and will not share your personal information without your express consent. For more information, please refer to our Privacy Policy. Subscribe to eTOC Secondary Logo Journal Logo All Articles Images Videos Podcasts Blogs Advanced Search Toggle navigation Subscribe Register Login Articles & Issues Current IssuePrevious IssuesPublished Ahead-of-Print CollectionsFor Authors Submit a ManuscriptInformation for AuthorsLanguage Editing ServicesAuthor PermissionsPublish Supplemental Issue Journal Info About the JournalEditorial BoardAdvertisingOpen AccessSubscription ServicesReprintsRights and Permissions All Articles Images Videos Podcasts Blogs Advanced Search

Virological and immunological characteristics of HIV treatment failure

Resistance to antiretroviral treatment is prevalent. There is limited knowledge of the determinants of disease evolution in subjects infected with multidrug-resistant HIV (MDR-HIV). Infectivity, replication, chemokine receptor usage, and env, gag, protease and reverse transcriptase sequence analysis was performed for MDR-HIV isolates from 14 HIV-infected individuals and compared to wild-type HIV isolates from individuals naive to antiretroviral treatment. Expression of CD45RO/RA, Ki67 and interferon-gamma and CD4 proliferative response to various antigens was determined for individuals infected with MDR-HIV and compared to that in individuals with optimal suppression of viral replication. Infectivity and replication are diminished for various MDR-HIV isolates, usually in the context of an increase in CD4 and CD4+CD45RA+ T-cell counts. However, a number of MDR-HIV isolates are associated with high in vivo viraemia and pronounced immunosuppression, and display in vitro levels of infectivity and replication comparable to those of wild-type strains. No specific genetic sequence or chemokine receptor usage predicted the fitness of an MDR isolate. Despite the biological diversity of resistant viruses and the range of host responses observed, our descriptive analysis indicates that viral factors play a role in determining the degree of immune damage observed in the context of MDR-HIV infection.

P20 Triple protease inhibitor combinations in patients with multidrug resistant HIV infection

P20 Triple protease inhibitor combinations in patients with multidrug resistant HIV infection