Prevalence of HIV drug resistance mutation in the northern Indian population after failure of the first line antiretroviral therapy.

There is limited information available about the prevalence and pattern of human immunodeficiency virus (HIV) drug resistance mutations (DRMs) among antiretroviral therapy (ART) experienced patients from northern India. Results of genotypic drug resistance testing were obtained from plasma samples of 128 patients, who had presented with clinical or immunological failure to treatment after at least six months of ART. Major DRMs associated with any of the three classes of antiretroviral (ARV) drugs, nucleoside reverse transcriptase inhibitors (NRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI), were seen in 120 out of 128 patients (93.8% prevalence). NRTI and NNRTI DRMs were each seen in 115/128 (89.8%) patients, with M184V, M41L, D67N and T215Y being the most frequent among NRTI associated mutations, and K103N, G190A, Y181C and A98G among NNRTI associated ones. PI DRMs were observed in 14/128 (10.9%) patients, with L10I, V82A and L89V being the commonest. These results present a high prevalence of DRMs among ART experienced patients from northern India with clinical or immunological failure of therapy. It emphasizes the need for regular testing of plasma samples of such patients for DRMs in order to detect and replace a failing regimen early, and also the use of HIV drug resistance genotyping of ART naive individuals prior to initiating first line ART for possible transmitted resistance. It is very important to enhance the access of patients to ARV drugs so that their compliance could be improved and hence development of DRMs be minimized.

Prevalence of HIV Drug Resistance Mutations in HIV Type 1 Isolates in Antiretroviral Therapy Naïve Population from Northern India.

Objective. The increased use of antiretroviral therapy (ART) has reduced the morbidity and mortality associated with HIV, adversely leading to the emergence of HIV drug resistance (HIVDR). In this study we aim to evaluate the prevalence of HIVDR mutations in ART-naive HIV-1 infected patients from northern India. Design. Analysis was performed using Viroseq genotyping system based on sequencing of entire protease and two-thirds of the Reverse Transcriptase (RT) region of pol gene. Results. Seventy three chronic HIV-1 infected ART naïve patients eligible for first line ART were enrolled from April 2006 to August 2008. In 68 patients DNA was successfully amplified and sequencing was done. 97% of HIV-1 strains belonged to subtype C, and one each to subtype A1 and subtype B. The overall prevalence of primary DRMs was 2.9% [2/68, 95% confidence interval (CI), 0.3%-10.2%]. One patient had a major RT mutation M184V, known to confer resistance to lamivudine, and another had a major protease inhibitor (PI) mutation D30N that imparts resistance to nelfinavir. Conclusion. Our study shows that primary HIVDR mutations have a prevalence of 2.9% among ART-naive chronic HIV-1 infected individuals.

Interleukin-2 therapy in patients with HIV infection.

BACKGROUND: Used in combination with antiretroviral therapy, subcutaneous recombinant interleukin-2 raises CD4+ cell counts more than does antiretroviral therapy alone. The clinical implication of these increases is not known. METHODS: We conducted two trials: the Subcutaneous Recombinant, Human Interleukin-2 in HIV-Infected Patients with Low CD4+ Counts under Active Antiretroviral Therapy (SILCAAT) study and the Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT). In each, patients infected with the human immunodeficiency virus (HIV) who had CD4+ cell counts of either 50 to 299 per cubic millimeter (SILCAAT) or 300 or more per cubic millimeter (ESPRIT) were randomly assigned to receive interleukin-2 plus antiretroviral therapy or antiretroviral therapy alone. The interleukin-2 regimen consisted of cycles of 5 consecutive days each, administered at 8-week intervals. The SILCAAT study involved six cycles and a dose of 4.5 million IU of interleukin-2 twice daily; ESPRIT involved three cycles and a dose of 7.5 million IU twice daily. Additional cycles were recommended to maintain the CD4+ cell count above predefined target levels. The primary end point of both studies was opportunistic disease or death from any cause. RESULTS: In the SILCAAT study, 1695 patients (849 receiving interleukin-2 plus antiretroviral therapy and 846 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 202 cells per cubic millimeter were enrolled; in ESPRIT, 4111 patients (2071 receiving interleukin-2 plus antiretroviral therapy and 2040 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 457 cells per cubic millimeter were enrolled. Over a median follow-up period of 7 to 8 years, the CD4+ cell count was higher in the interleukin-2 group than in the group receiving antiretroviral therapy alone--by 53 and 159 cells per cubic millimeter, on average, in the SILCAAT study and ESPRIT, respectively. Hazard ratios for opportunistic disease or death from any cause with interleukin-2 plus antiretroviral therapy (vs. antiretroviral therapy alone) were 0.91 (95% confidence interval [CI], 0.70 to 1.18; P=0.47) in the SILCAAT study and 0.94 (95% CI, 0.75 to 1.16; P=0.55) in ESPRIT. The hazard ratios for death from any cause and for grade 4 clinical events were 1.06 (P=0.73) and 1.10 (P=0.35), respectively, in the SILCAAT study and 0.90 (P=0.42) and 1.23 (P=0.003), respectively, in ESPRIT. CONCLUSIONS: Despite a substantial and sustained increase in the CD4+ cell count, as compared with antiretroviral therapy alone, interleukin-2 plus antiretroviral therapy yielded no clinical benefit in either study. (ClinicalTrials.gov numbers, NCT00004978 [ESPRIT] and NCT00013611 [SILCAAT study].)

Continuing medical education on antiretroviral therapy in HIV/AIDS in India: needs assessment and impact on clinicians and allied health personnel.

BACKGROUND: Clinicians and associated health professionals charged with prescribing antiretroviral therapy (ART) deal with continuously evolving new drugs and combinations. To meet the needs of clinicians in India for ongoing education in this field, continuing medical education (CME) programmes on ART for HIV/AIDS were developed, conducted, evaluated and revised. Over a 2-year period, 2005-2007, 3 CME programmes for ART were conducted for physicians and a fourth (predominantly) for paediatricians. METHODS: Both 1- and 2-day CME programmes on various aspects of ART were held on weekends for professionals treating patients with AIDS in Delhi and adjacent states. Topics included characteristics of ART drugs, their dosages, monitoring and toxicity management, adherence, complications of therapy, dealing with treatment failure and HIV co-infections. These topics were addressed in lectures and group discussions and via case presentations. Programmes were evaluated by anonymous response to questionnaires, by a 1-year follow up of participants and by informal discussions with participants and faculty. Detailed analyses and a recommended format for these programmes are presented. RESULTS: The CMEs were attended primarily by clinicians (physicians and paediatricians). Nurses, laboratory scientists, and others involved in the treatment of AIDS also attended the programmes. An interactive workshop format was evolved with substantial time devoted to discussions and case analyses. One-day programmes such as the one included here can be comprehensive and effective. The educational needs of healthcare professionals who provide care and support to patients receiving ART were similar to those of the prescribing doctors. Because of new drugs being made available and with continued clinical experience, updated programme content was required each year. Participants preferred case-based interactive discussions rather than didactic lectures. Participants suggested that there should be more time for discussion after each talk. CONCLUSION: Annual CME programmes focused on ART are required to meet the professional needs of clinicians in India for providing quality care management to patients with AIDS.

The potential role of interleukin-2 in HIV.

Interleukin-2 (IL-2) is a secretory cytokine produced by activated T cells that stimulates T cells, B cells, and natural killer cells to proliferate and release cytokines. In addition, IL-2 slows apoptosis of HIV-infected cells. Clinical studies have demonstrated that exogenous human recombinant IL-2 can be safely administered concurrently with potent antiretroviral therapy to HIV-infected patients. It was further demonstrated that recombinant human IL-2 therapy produces sustained increases in CD4+ cell number and function in patients with both early and late HIV disease. Further evaluation of the clinical efficacy of IL-2 in HIV-infected patients is expected to provide important information on the utility of recombinant human IL-2 in HIV disease.

Two double-blinded, randomized, comparative trials of 4 human immunodeficiency virus type 1 (HIV-1) envelope vaccines in HIV-1-infected individuals across a spectrum of disease severity: AIDS Clinical Trials Groups 209 and 214.

The potential role of human immunodeficiency virus type 1 (HIV-1)-specific immune responses in controlling viral replication in vivo has stimulated interest in enhancing virus-specific immunity by vaccinating infected individuals with HIV-1 or its components. These studies were undertaken to define patient populations most likely to respond to vaccination, with the induction of novel HIV-1-specific cellular immune responses, and to compare the safety and immunogenicity of several candidate recombinant HIV-1 envelope vaccines and adjuvants. New lymphoproliferative responses (LPRs) developed in <30% of vaccine recipients. LPRs were elicited primarily in study participants with a CD4 cell count >350 cells/mm(3) and were usually strain restricted. Responders tended to be more likely than nonresponders to have an undetectable level of HIV-1 RNA at baseline (P=.067). Induction of new cellular immune responses by HIV-1 envelope vaccines is a function of the immunologic stage of disease and baseline plasma HIV-1 RNA level and exhibits considerable vaccine strain specificity.

Pooled analysis of 3 randomized, controlled trials of interleukin-2 therapy in adult human immunodeficiency virus type 1 disease.

We collected human immunodeficiency virus (HIV) disease progression, survival, most recent CD4 cell count, and plasma HIV RNA levels from patients (n=157) who participated in randomized clinical trials of interleukin (IL)-2 that commenced before 1995. Data were available for 155 (99%) patients. Statistical analyses were based on the intention-to-treat principle. Median follow-up was 28 months and 30 months for control and IL-2 patients, respectively. Twenty-five (16%) patients developed AIDS or died during follow-up (16 control patients vs. 9 IL-2 patients; R2=0.57; P=.22). Mean change from baseline CD4 cell count was significantly higher in patients randomized to receive IL-2 (368 vs. 153 cells/microL; P=.003). Mean change from baseline plasma HIV RNA was significantly lower in patients randomized to receive IL-2 (-0.98 vs. -0.63 log copies/mL; P=.004). Significant improvements in CD4 cell count and plasma HIV RNA in recipients of IL-2 relative to control patients were associated with a nonsignificant trend toward improved clinical outcome.

Prolonged survival and tissue trafficking following adoptive transfer of CD4zeta gene-modified autologous CD4(+) and CD8(+) T cells in human immunodeficiency virus-infected subjects.

We have genetically engineered CD4(+) and CD8(+) T cells with human immunodeficiency virus (HIV) specificity by inserting a gene, CD4zeta, containing the extracellular domain of human CD4 (which binds HIV env) linked to the zeta (zeta) chain of the T-cell receptor (which mediates T-cell activation). Twenty-four HIV-positive subjects received a single infusion of 2 to 3 x 10(10) autologous CD4zeta-modified CD4(+) and CD8(+) T cells administered with (n = 11) or without (n = 13) interleukin-2 (IL-2). Subjects had CD4 counts greater than 50/microL and viral loads of at least 1000 copies/mL at entry. T cells were costimulated ex vivo through CD3 and CD28 and expanded for approximately 2 weeks. CD4zeta was detected in 1% to 3% of blood mononuclear cells at 8 weeks and 0.1% at 1 year after infusion, and survival was not enhanced by IL-2. Trafficking of gene-modified T cells to bulk rectal tissue and/or isolated lamina propria lymphocytes was documented in a subset of 5 of 5 patients at 14 days and 2 of 3 at 1 year. A greater than 0.5 log mean decrease in rectal tissue-associated HIV RNA was observed for at least 14 days, suggesting compartmental antiviral activity of CD4zeta T cells. CD4(+) counts increased by 73/microL at 8 weeks in the group receiving IL-2. There was no significant mean change in plasma HIV RNA or blood proviral DNA in either treatment arm. This sustained, high-level persistence of gene-modified T cells demonstrates the feasibility of ex vivo T-cell gene therapy in HIV-infected adults and suggests the importance of providing HIV-specific T-helper function.

AIDS-related Kaposi's sarcoma: current treatment options, future trends.

Kaposi's sarcoma (KS) is the most common malignancy associated with the acquired immunodeficiency syndrome (AIDS). Recent years have witnessed a decline in the overall incidence of AIDS-related KS, as well as a greater understanding of the pathogenesis of this disease. Despite these occurrences, AIDS-related KS remains an incurable disease that can create many psychosocial problems for patients and can adversely affect their quality of life. Clinical management of AIDS-related KS has proven to be challenging. Traditional treatment approaches for both local and visceral lesions have been palliative in intent. Clinical studies have shown alitretinoin gel (Panretin) to be a useful alternative or adjunct to other treatments for the management of cutaneous KS lesions. Other therapies, such as antiangiogenesis compounds and cytokine inhibitors, are under investigation in clinical trials, and pathogenesis-directed therapies, such as anti-human herpesvirus type 8 agents, show promise for the effective control of this disease. This review highlights the epidemiology and pathogenesis of AIDS-related KS, and describes various local and systemic therapies, with a focus on new and emerging treatments.

Evidence that anoreceptive intercourse with ejaculate exposure is associated with rapid CD4 cell loss.

OBJECTIVE: To determine whether ejaculate exposure through anoreceptive intercourse is associated with rapid CD4 cell loss. DESIGN: Self-reported behavioral, demographic data and blood samples were gathered longitudinally at ten semiannual visits from individuals participating in the Multicenter AIDS Cohort Study (MACS). PATIENTS/PARTICIPANTS: A group of 937 HIV-seropositive men who were continuously followed for four to ten semiannual visits. OUTCOME MEASURES: A loss of 10% or more in CD4 cells between the first two of any three consecutive semiannual visits that was followed by a 10% or greater loss between the second and third visits. RESULTS: A period of rapid CD4 cell loss over three semiannual visits occurred in 389 of the 937 (42%) HIV-seropositive men studied. Men who reported one or more anoreceptive intercourse partners with whom they were exposed to ejaculate (RAI-E) during the 12 months immediately preceding their visits were more than twice as likely to show this rapid CD4 cell loss compared with men with no such partners. CONCLUSIONS: The association between RAI-E partnerships and rapid CD4 cell loss suggests factors associated with ejaculate exposure (e.g., sexually transmitted diseases) may hasten the clinical progression of HIV disease. It is suggested that infectious diseases, which are known to be associated with ejaculate exposure, may be the causal factor underlying the association between RAI-E partnerships and rapid CD4 cell loss in these men, although the presence of these diseases was not ascertained in these data. HIV-infected individuals should be cautioned against unprotected anoreceptive intercourse.

Update on the pathogenesis and treatment of Kaposi sarcoma.

Kaposi sarcoma (KS), an unusual tumor of vascular origin, was one of the first recognized manifestations of AIDS. In the past few years, it has become clear that human herpesvirus-8 (HHV-8) is critical to the development of KS in the setting of immunosuppression, such as that seen with HIV infection. Other genetic and environmental factors may also play a role in the pathogenesis of KS. Of note, several endogenous substances elaborated by HIV-infected cells may promote angiogenesis and the growth of KS. With advances in our understanding of the pathogenesis of this tumor have come novel treatments for KS. Suppression of HIV replication has substantially decreased the incidence of KS in the western world, and treatment directed at angiogenesis or virus-induced tumorigenesis may ultimately lead to more effective control of KS. For most patients, however, standard chemotherapy, radiation therapy, topical therapies, and interferon-alpha remain the mainstays of treatment. In this review, recent advances in our understanding of the pathogenesis of KS are highlighted and a brief overview of current approaches to the treatment of this tumor is provided.

Prevention of bacterial infections in patients with advanced HIV infection.

In a study of 258 moderately neutropenic HIV-infected patients, Filgrastim (recombinant methionyl human granulocyte colony-stimulating factor) treatment significantly reduced the incidence of severe neutropenia and bacterial infections. Filgrastim-treated patients also had 54% fewer severe bacterial infections and 45% fewer days in hospital for any bacterial infections. No unexpected or new adverse events were observed and there were no differences in plasma HIV-1 RNA levels between the groups.

HIV protease inhibitors: immunological insights.

Regimens of highly active antiretroviral therapy (HAART), including those containing one or more of the potent HIV protease inhibitors, often cause large increases in CD4 cell count as well as large decreases in plasma HIV RNA that persist over time. Patients improve clinically, and the occurrence (or recurrence) of opportunistic diseases appears to be reduced. This raises issues about the source and functional capacity of the CD4 cells seen in patients receiving HAART. This article briefly summarizes the current information about the recirculation of T cells from lymphoid tissue to blood after HAART, increases in the number of naive (CD45RA+, CD62L+) and memory (CD45RO+) CD4 cells, changes in the T cell repertoire (Vbeta), and the possible role of selected cytokines that may be useful in facilitating immune reconstitution in patients receiving HAART. Preliminary data from some studies have revealed that, after several months of therapy, the number of memory CD4 cells increased, followed by increases in naive CD4 cells. Other studies have found that the number of naive CD4 cells increases only if these cells were present before initiation of therapy and that disruptions of the Vbeta subsets are not immediately corrected. Studies concerning the relations of various cytokines to immune reconstitution are also ongoing. On the basis of the limited results available in late 1997, there is good reason to hope for at least partial immune reconstitution in HIV patients treated with HAART, especially if therapy is initiated before severe damage to the immune system has occurred. In the future, cytokines such as interleukin-2, vaccinations, cellular replacement or stem cell transfer, or bone marrow transplants may play important roles in therapy.

Oncological complications of human immunodeficiency virus disease and hematologic consequences of their treatment.

Despite advances in antiretroviral therapy and in the treatment and prevention of opportunistic infections, oncological and consequent hematologic complications of human immunodeficiency virus (HIV) infection continue to occur and are of significant clinical importance. Virus-related tumors (e.g., Kaposi's sarcoma, induced by human herpesvirus 8; non-Hodgkin's lymphoma, linked to Epstein-Barr virus; and anogenital tumors, linked to human papillomavirus) are frequent in patients with HIV-induced immune deficiency. The incidence of AIDS-related Kaposi's sarcoma has declined among homosexual men, but this tumor remains problematic in many patients. Non-Hodgkin's lymphoma is 60 times more prevalent in HIV-positive persons than in others and typically presents as advanced-stage, high- or intermediate-grade B cell lymphoma, with frequent extranodal involvement. Primary central nervous system lymphoma is also common. Cervical carcinoma in HIV-positive women is also usually advanced at diagnosis. Anal carcinoma is increasing in both HIV-positive and HIV-negative populations. Chemotherapy for these tumors can result in dose-limiting cytopenia that can be well-controlled with hematopoietic growth factors, allowing patients to avoid transfusions and maintain the dose intensity of their chemotherapy regimens.

Initial increase in blood CD4(+) lymphocytes after HIV antiretroviral therapy reflects redistribution from lymphoid tissues.

Previous studies proposed a dynamic, steady-state relationship between HIV-mediated cell killing and T-cell proliferation, whereby highly active antiretroviral therapy (HAART) blocks viral replication and tips the balance toward CD4(+) cell repopulation. In this report, we have analyzed blood and lymph node tissues obtained concurrently from HIV-infected patients before and after initiation of HAART. Activated T cells were significantly more frequent in lymph node tissue compared with blood at both time points. Ten weeks after HAART, the absolute number of lymphocytes per excised lymph node decreased, whereas the number of lymphocytes in the blood tended to increase. The relative proportions of lymphoid subsets were not significantly changed in tissue or blood by HAART. The expression levels of mRNA for several proinflammatory cytokines (IFN-gamma, IL-1beta, IL-6, and macrophage inflammatory protein-1alpha) were lower after HAART. After therapy, the expression of VCAM-1 and ICAM-1 -- adhesion molecules known to mediate lymphocyte sequestration in lymphoid tissue -- was also dramatically reduced. These data provide evidence suggesting that initial increases in blood CD4(+) cell counts on HAART are due to redistribution and that this redistribution is mediated by resolution of the immune activation that had sequestered T cells within lymphoid tissues.

Gene therapy for the treatment of AIDS: animal models and human clinical experience.

Although antiretroviral drug therapy has had a significant impact on the natural history of HIV infection, complete virus eradication still remains an unattainable goal. Drug-mediated virological control only occurs transiently, in part as a result of the development of drug resistance. Gene therapy for the treatment of AIDS is a promising area of research that has as its goal the replacement of the HIV-infected cellular pool with cells engineered to resist virus replication. A variety of anti-HIV genes have been designed and tested in laboratory systems, and available results from pilot clinical trials demonstrate the safety and feasibility of this approach. Obstacles to effective application of this technology include partial protection of HIV resistance genes, lack of effective vectoring systems, and unregulated gene expression. Herein, we review recent advances in transduction methods, data from in vivo preclinical studies in relevant animal models, and emerging results derived from pilot clinical gene therapy studies.