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.

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.

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.

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.

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.

Stability of plasma levels of cytokines and soluble activation markers in patients with human immunodeficiency virus infection.

Cytokine and immune activation marker levels in plasma are valuable measurements of immune status and treatment effects in human immunodeficiency virus (HIV) infection and AIDS. Five populations representing various stages of disease were studied: controls, 2 AIDS groups with <50/mm3 CD4 cells, and 2 groups of HIV-positive subjects-1 with stable CD4 T cells (median, 545/mm3) and 1 with >100/mm3 CD4 cell decline in 1 year. Relatively stable levels of tumor necrosis factor (TNF)-alpha, soluble TNF receptor (R)II, soluble interleukin-2R, neopterin, and beta2-microglobulin (beta2M) were documented over 5-8 weeks in patients with AIDS and for 1-4 years in the other groups. beta2M was generally the most stable marker. Interferon-gamma levels, however, fluctuated substantially. Individuals, whether normal or HIV-positive, maintain characteristic plasma levels of cytokines and immune activation markers. Thus, documented changes, in excess of the variability observed in this study, are likely to be significant indicators of change in disease status or effects of therapy.

Activity of the soft gelatin formulation of saquinavir in combination therapy in antiretroviral-naive patients. NV15355 Study Team.

OBJECTIVE: A Phase II, open-label, randomized, parallel-arm, multicentre trial to compare the antiviral activity and safety of two formulations of saquinavir (SQV), soft gelatin (SQV-SGC) and hard gelatin (SQV-HGC) capsules, in combination with two nucleoside reverse transcriptase inhibitors (NRTI), in antiretroviral-naive, HIV-1-infected individuals. PARTICIPANTS: A total of 171 people of > or = 13 years, with plasma HIV-1 RNA levels > or = 5000 copies/ml, who had received no protease inhibitor therapy, < or = 4 weeks NRTI therapy and no antiretroviral treatment within 28 days of screening. Eighty-one people were randomized to the SQV-HGC group and 90 to the SQV-SGC group. A total of 148 patients completed 16 weeks of therapy. INTERVENTION: Therapy for 16 weeks with either SQV-SGC 1200 mg or SQV-HGC 600 mg, both three times a day, in combination with two NRTI. RESULTS: Using an on-treatment analysis, patients taking SQV-SGC had a larger reduction in plasma HIV-1 RNA than those taking SQV-HGC (-2.0 versus -1.6 log10 copies/ml). Eighty per cent of those on SQV-SGC had < 400 copies HIV RNA/ml, compared with 43% in the SQV-HGC group (P = 0.001). A statistically significant difference in the area under the curve (AUC) values between the SQV-SGC and SQV-HGC arms (-1.7 versus -1.5 log10 copies/ml, respectively; P = 0.0054) was observed when withdrawals prior to week 12, major protocol violators and patients with < 75% compliance were excluded from the analysis; however, the difference between the values for the intent-to-treat population was not significant (P = 0.1929). Adverse events (mostly mild) included diarrhoea and nausea. CONCLUSIONS: SQV-SGC was generally well tolerated and gave significantly more potent suppression of plasma HIV-1 RNA in antiretroviral-naive patients than SQVHGC.

Use of interleukin-2 in immunotherapy of human immunodeficiency virus infection.

Interleukin-2 (IL-2) is a cytokine produced by activated T cells. Its stimulatory activity allows T cells, B cells and natural killer cells to proliferate and to release cytokines and antibodies which protect the host against invading organisms. IL-2 plays a critical role in the prevention of apoptosis of HIV-infected cells, and the addition of IL-2 to a culture medium will increase the survival of T cells and will upregulate IL-2 receptor function. Clinical studies of the administration of exogenous IL-2 to HIV-infected patients have demonstrated that it can be given in well tolerated doses and that it can increase and sustain the number of CD4+ cells while only transiently affecting viral proliferation, especially when given to patients with CD4+ counts >200 cells/mm(3). Further investigations are required to determine the optimal use of exogenous IL-2 in HIV-infected patients. There may also be an important role for IL-2 as an adjunct to gene therapy and preventive vaccines against HIV infection.

AIDS Clinical Trials Group Study 094: a phase I/II trial of ABV chemotherapy with zidovudine and recombinant human GM-CSF in AIDS-related Kaposi's sarcoma.

PURPOSE: To define the maximum tolerated dose of doxorubicin when combined with fixed doses of bleomycin, vincristine, zidovudine, and recombinant human granulocyte macrophage colony-stimulating factor (rhGM-CSF) in patients with advanced AIDS-related Kaposi's sarcoma. PATIENTS AND METHODS: Twenty male patients were treated with zidovudine at doses of either 100 or 200 mg by mouth every 4 hours, and cytotoxic chemotherapy with bleomycin 10 U/m2 and vincristine 1.4 mg/m2 by vein every 2 weeks. Four successive cohorts received fixed doses of doxorubicin given intravenously every 2 weeks: two cohorts each received 10 mg/m2 (levels 1, 2) or 20 mg/m2 (levels 3, 4). The first cohort received rhGM-CSF at a dose of 10 micrograms/ kg, given subcutaneously on days 2 through 11 (level 1). Due to toxicity, the dose of rhGM-CSF was reduced to 5 micrograms/kg (levels 2, 3) and then to 2.5 micrograms/kg (level 4). RESULTS: The dose-limiting toxicity was severe neutropenia, occurring in 10 patients. Severe neutropenic episodes occurred after a median of three cycles of chemotherapy, with the nadir occurring after 14 days (median). Moderate neutropenia occurred in 14% of all cycles administered. Constitutional toxicities of moderate or greater severity occurred in four patients. Five of 10 patients at a doxorubicin dose of 20 mg/m2 (levels 3 and 4) experienced severe neutropenia. Thus, doxorubicin at 10 mg/m2, with BV (bleomycin, vincristine chemotherapy), zidovudine (100 mg five times daily), and rhGM-CSF (5 micrograms/kg/day), was defined as the maximum tolerated dose. CONCLUSIONS: The maximum tolerated dose of doxorubicin is 10 mg/ m2 every 2 weeks when given in combination with BV chemotherapy, zidovudine, and rhGM-CSF. While the addition of rhGM-CSF at doses of 2.5 to 5 micrograms/kg decreased the duration of neutropenia, it did not prevent the occurrence of severe neutropenia from combined myelotoxic therapy.

Randomised trial of MNrgp120 HIV-1 vaccine in symptomless HIV-1 infection.

BACKGROUND: Most individuals infected with HIV-1 show disease progression despite both cellular and humoral immune responses. We investigated whether immunisation of patients who had symptomless HIV-1 infection with an envelope subcomponent vaccine (MNrgp120) to augment immune response can slow progression of HIV-1 disease. METHODS: In a randomised, double-blind, placebo-controlled trial, carried out in university infectious disease clinics and community infectious disease practices, we enrolled 573 HIV-infected patients with CD4 counts above 600 cells/microL (0.6 x 10(9)/L). Patients received 600 micrograms vaccine or placebo by intramuscular injection monthly for 6 months then every alternate month throughout the study. The primary endpoint was the rate of decline in CD4 count; secondary endpoints were HIV-1 RNA concentrations in plasma and minor clinical events associated with HIV. Analysis was by intention to treat. FINDINGS: At baseline, the study participants had a mean CD4 count of 775 cells/microL (SD 172) and 89% of participants had detectable HIV RNA (> 200 copies/mL). These RNA-positive individuals had a median viral load of 9250 copies/mL (IQR 2670-26960). Analysis after 15 months of follow-up of the 568 subjects who had at least one CD4 count done after randomisation showed no difference between the 287 vaccine recipients and 281 placebo recipients in rate of decline of CD4 count (yearly decrease 53.8 [SE 7.6] vs 42.3 [7.6] cells/microL; ratio of mean gradients 1.27 [95% CI 0.63-2.55]) or in plasma HIV-1 RNA concentrations (p > or = 0.63). The study was designed with power to detect a vaccine-induced reduction in rate of decline in CD4 count of 60%; these results exclude with 95% confidence a reduction of 40% or more. More vaccine-treated patients than placebo recipients showed a 50% decrease in CD4 count (11 vs 5; relative risk 2.15 [95% CI 0.76-6.12], p = 0.13). The frequencies of HIV-related minor clinical events were similar in the two groups. Pain at the injection site was the only adverse event that occurred more frequently in vaccine-treated group. INTERPRETATION: Postinfection immunisation of symptom-free HIV-infected patients with MNrgp120 vaccine did not alter HIV-1 disease progression as measured by immunological, virological, and clinical endpoints over a 15-month period.

Chemotherapy of AIDS--related Kaposi's sarcoma.

Kaposi's sarcoma (KS) is the most common tumor associated with AIDS. A growing number of patients with this tumor are presenting at later stages of HIV with more rapidly progressive, extensive, or symptomatic KS or with tumors involving visceral organs. Chemotherapy treatment is effective in inducing tumor regression, reducing edema, and ameliorating symptoms caused by these tumors. Side effects and toxicities from these agents, however, can be quite pronounced, especially in patients with advanced AIDS Antiretroviral therapy, prophylaxis for opportunistic infections, and the use of hematopoietic growth factors should be routinely included in the management of these patients. Newer chemotherapeutic agents and combination regimens may be more effective or less toxic than previously evaluated regimens.

Pathogenesis of AIDS--related Kaposi's sarcoma.

The occurrence of Kaposi's sarcoma (KS) in patients with HIV infection is more than 7,000 times higher than in the non-HIV infected population. The reason for this association is unclear but may involve decreased immune surveillance as a result of the profound cellular immune deficiency caused by HIV, a sexually transmitted KS-inducing virus, whose KS-transforming capabilities may be enhanced by HIV, or a direct or indirect effect of HIV itself in susceptible individuals. Over the last few years, advances have been made in our understanding of the pathogenesis of this tumor, and several models have been proposed for its development in the setting of AIDS. Better characterization of the processes involved in the development of KS will ultimately lead to more effective methods of treating and preventing this unusual tumor.

Phase I AIDS Clinical Trials Group (075) study of adriamycin, bleomycin and vincristine chemotherapy with zidovudine in the treatment of AIDS-related Kaposi's sarcoma.

OBJECTIVE: To determine the toxicity and maximum tolerated dose of doxorubicin (adriamycin) in combination with fixed doses of bleomycin, vincristine (ABV) and zidovudine in patients with advanced AIDS-related Kaposi's sarcoma. PATIENTS AND METHODS: Twenty-six HIV-seropositive men with Kaposi's sarcoma were treated daily with 100 mg zidovudine orally every 4 h, along with combination chemotherapy using bleomycin 10 U/m2 and vincristine 1.4 mg/m2 (maximum, 2 mg) given intravenously in 2-week cycles. In addition, three successive cohorts of eight patients received escalating doses of doxorubicin each beginning with no doxorubicin (level I), doses of 10 mg/m2 (level II), and 15 mg/m2 (level III). RESULTS: The major dose-limiting toxicity experienced with the combination therapy was severe neutropenia in eight patients, four of whom received level III doxorubicin (15 mg/m2). Therefore, 10 mg/m2 of doxorubicin in combination with zidovudine and BV chemotherapy was defined as the maximum tolerated dose. Other dose-limiting toxicities included neuropathy (n = 2), cutaneous toxicity associated with bleomycin (n = 1), and diarrhea (n = 1). Seventeen patients (71%; 95% confidence interval, 46-85) experienced either partial (n = 13) or clinical complete remission (n = 4) to therapy after a median of five cycles (range, 2-9). CONCLUSION: The maximum tolerated dose of doxorubicin is 10 mg/m2 when given in combination with zidovudine and BV chemotherapy. Response rates observed with the combined antiretroviral and chemotherapy regimen are similar to those previously reported with ABV chemotherapy alone.