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Biomedical subjects

David A Katzenstein

Publications and source records attributed to David A Katzenstein.

At least 19 recordsLinked to original sources
PubMed2006

Treatment for adult HIV infection: 2006 recommendations of the International AIDS Society-USA panel.

CONTEXT: Guidelines for antiretroviral therapy are important for clinicians worldwide given the complexity of the field and the varied clinical situations in which these agents are used. The International AIDS Society-USA panel has updated its recommendations as warranted by new developments in the field. OBJECTIVE: To provide physicians and other human immunodeficiency virus (HIV) clinicians with current recommendations for the use of antiretroviral therapy in HIV-infected adults in circumstances for which there is relatively unrestricted access to drugs and monitoring tools. The recommendations are centered on 4 key issues: when to start antiretroviral therapy; what to start; when to change; and what to change. Antiretroviral therapy in special circumstances is also described. DATA SOURCES AND STUDY SELECTION: A 16-member noncompensated panel was appointed, based on expertise in HIV research and patient care internationally. Data published or presented at selected scientific conferences from mid 2004 through May 2006 were identified and reviewed by all members of the panel. DATA EXTRACTION AND SYNTHESIS: Data that might change previous guidelines were identified and reviewed. New guidelines were drafted by a writing committee and reviewed by the entire panel. CONCLUSIONS: Antiretroviral therapy in adults continues to evolve rapidly, making delivery of state-of-the-art care challenging. Initiation of therapy continues to be recommended in all symptomatic persons and in asymptomatic persons after the CD4 cell count falls below 350/microL and before it declines to 200/microL. A nonnucleoside reverse transcriptase inhibitor or a protease inhibitor boosted with low-dose ritonavir each combined with 2 nucleoside (or nucleotide) reverse transcriptase inhibitors is recommended with choice being based on the individual patient profile. Therapy should be changed when toxicity or intolerance mandate it or when treatment failure is documented. The virologic target for patients with treatment failure is now a plasma HIV-1 RNA level below 50 copies/mL. Adherence to antiretroviral therapy in the short-term and the long-term is crucial for treatment success and must be continually reinforced.

Adult↗
PubMed2006

Affordable flow cytometry for enumeration of absolute CD4+ T-lymphocytes to identify subtype C HIV-1 infected adults requiring antiretroviral therapy (ART) and monitoring response to ART in a resource-limited setting.

BACKGROUND: The World Health Organization (WHO)'s "3 x 5 program" has spurred efforts to place 3 million people on combination antiretroviral therapy (ART) for treatment of AIDS in resource-limited countries. Paradoxically, the cost of CD4+ T-lymphocyte count essential for decision-making to commence HIV positive adults on ART as well as for monitoring responses to ART remains unaffordable in most resource-limited countries. Thus, low-cost methods for enumerating CD4+ T-lymphocyte are urgently needed. OBJECTIVE: To evaluate Cyflow cytometry (Cyflow SL, Partec, Munster, Germany) for enumeration of absolute CD4+ T-lymphocyte in subtype C HIV-1 seropositive subjects using FACSCount (Becton and Dickinson, Immunocytometry Systems, San Jose, CA, USA) as the "predicate method". METHODS: A total of 150 HIV-1 seropositive subjects were included in the evaluation exercise. Fifty-eight specimens were collected from pregnant HIV-1 seropositive women (subtype C drug resistance study). Twenty-seven specimens were collected from women and their spouses with AIDS followed in a Duke ART study to assess the immunologic and virologic responses to generic ART, comprising Stavudine, Lamivudine and Nevirapine (Stalanev, Varichem Labs, Harare, Zimbabwe). Sixty-five specimens were collected from AIDS patients enrolled in an ongoing Kaposi Sarcoma (KS) study to investigate impact of ART on KS progression. Enumeration of CD4+ T-lymphocytes using FACSCount is routinely conducted for all the three studies. The Medical Research Council of Zimbabwe and Medicines Control Authority of Zimbabwe approved the studies. Whole blood was collected in EDTA vacutainer tubes and aliquoted into two tubes (200 microL in each). CD4+ T-lymphocyte counts were enumerated using a Cyflow counter, in the Department of Immunology and a FACSCount in the Department of Obstetrics and Gynaecology within 6 hours of phlebotomy following manufacturers' instructions. RESULTS: Using linear regression analysis, there was a very strong correlation (R = 0.991) between the overall CD4+ T-lymphocyte counts obtained by FACSCount and those obtained by Cyflow. When data analysis was stratified by study groups, there was a strong correlation between the FACSCount and Cyflow CD4+ T-lymphocyte counts from subjects in the three independent studies; Subtype C resistance (R2 = 0.987), Duke ART (R2 = 0.980) and KS (R2 = 0.994), Table 1. Using Bland-Altman plots, the overall, absolute CD4+ T lymphocytes obtained by the two methods were in excellent agreement (mean difference 1.21, 95% Confidence Interval {CI): -2.1 to 3.3). For the 0-250 CD4+ T-lymphocytes range, the CD4 counts obtained using FACSCount were also in good agreement with those obtained using Cyflow counter (mean difference = 2.6 cells/microL, 95% CI: -1.1 to 6.3). Similarly, in the 251-500 (mean difference 1.0, cells/microL, 95% CI: -3.7 to 5.6) and the 501-1200 (mean difference = 0.29 cells/microL, 95% CI: -8.1 to 8.7) CD4 T-lymphocytes range, good agreement was observed. CONCLUSION: The Cyflow counter is as accurate as the FACSCount in enumerating absolute CD4+ T-lymphocytes in the range 1-1200 cells/muL. Cyflow cytometry is relatively affordable, easy to use technology that is useful not only in identifying HIV seropositive individuals who require ART but also for monitoring immunologic responses to ART.

Journal Article↗
PubMed2006

HIV-1 pol mutation frequency by subtype and treatment experience: extension of the HIVseq program to seven non-B subtypes.

OBJECTIVE: HIVseq was developed in 2000 to make published data on the frequency of HIV-1 group M protease and reverse transcriptase (RT) mutations available in real time to laboratories and researchers sequencing these genes. Because most published protease and RT sequences belonged to subtype B, the initial version of HIVseq was based on this subtype. As additional non-B sequences from persons with well-characterized antiretroviral treatment histories have become available, the program has been extended to subtypes A, C, D, F, G, CRF01, and CRF02. METHODS: The latest frequency of each protease and RT mutation according to subtype and drug-class exposure was calculated using published sequences in the Stanford HIV RT and Protease Sequence Database. Each mutation was hyperlinked to published reports of viruses containing the mutation. RESULTS: As of September 2005, the mean number of protease sequences per non-B subtype was 534 from protease inhibitor-naive persons and 133 from protease inhibitor-treated persons, representing 13.2% and 2.3%, respectively, of the data available for subtype B. The mean number of RT sequences per non-B subtype was 373 from RT inhibitor-naive persons and 288 from RT inhibitor-treated persons, representing 17.9% and 3.8%, respectively, of the data available for subtype B. CONCLUSIONS: HIVseq allows users to examine protease and RT mutations within the context of previously published sequences of these genes. The publication of additional non-B protease and RT sequences from persons with well-characterized treatment histories, however, will be required to perform the same types of analysis possible with the much larger number of subtype B sequences.

Base Sequence↗
PubMed2005

Breast-milk shedding of drug-resistant HIV-1 subtype C in women exposed to single-dose nevirapine.

Single-dose nevirapine reduces intrapartum human immunodeficiency virus 1 type (HIV-1) transmission but may also select for nonnucleoside reverse-transcriptase inhibitor (NNRTI) resistance in breast milk (BM) and plasma. Among 32 Zimbabwean women, median 8-week postpartum plasma and BM HIV-1 RNA levels were 4.57 and 2.13 log(10) copies/mL, respectively. BM samples from women with laboratory-diagnosed mastitis (defined as elevated BM Na(+) levels) were 5.4-fold more likely to have HIV-1 RNA levels above the median. BM RT sequences were not obtained for 12 women with BM HIV-1 RNA levels below the lower limit of detection of the assay used. In 20 paired BM and plasma samples, 65% of BM and 50% of plasma RT sequences had NNRTI-resistance mutations, with divergent mutation patterns.

Anti-HIV Agents↗
PubMed2005

Signal-boosted qualitative ultrasensitive p24 antigen assay for diagnosis of subtype C HIV-1 infection in infants under the age of 2 years.

The gold standard for diagnosis of HIV-1 infection in infants under the age of 2 years is DNA or reverse transcriptase polymerase chain reaction. However, these tests are expensive and therefore not available in resource-limited countries. With the increasing availability of antiretroviral drugs for prevention of mother-to-child transmission of HIV and treatment of AIDS in resource-poor countries, there is an urgent need to develop cheaper, alternative, and cost-effective laboratory methods for early diagnosis of infant HIV-1 infection that will be useful in identifying infected infants who may benefit from early cotrimoxazole prophylaxis or commencement of antiretroviral therapy. We evaluated an alternative method, the enzyme-linked immunosorbent assay-based qualitative ultrasensitive p24 antigen assay for diagnosis of subtype C HIV-1 infection in infants under the age of 2 years using DNA polymerase chain reaction as the reference method. The assay showed a sensitivity of 96.7% (95% CI: 93.0-100) for detection of HIV-1 infection among infants 0-18 months of age with a specificity of 96.1% (95% CI: 91.7-100). These evaluated parameters were not statistically different between infants aged 0-6 and 7-18 months. The ultrasensitive p24 antigen assay is a useful diagnostic test for detection of HIV-1 infection among infants aged 0-18 months.

Enzyme-Linked Immunosorbent Assay↗
PubMed2005

Nonnucleoside reverse transcriptase inhibitor phenotypic hypersusceptibility can be demonstrated in different assays.

BACKGROUND: HIV-1 isolates harboring multiple nucleoside reverse transcriptase inhibitor (NRTI) resistance mutations are more susceptible ("hypersusceptible") to the nonnucleoside reverse transcriptase inhibitors (NNRTIs) than isolates lacking NRTI resistance mutations, but this has only been reported with a single-cycle replication phenotypic assay. In fact, there was a report that a commercial multicycle assay did not readily detect hypersusceptibility. OBJECTIVE: To see whether NNRTI hypersusceptibility can be demonstrated in other types of phenotypic assays, including multicycle assays and enzyme inhibition assays. METHODS: The susceptibility of HIV-1 clones derived from different patients in multicycle assays was tested in peripheral blood mononuclear cells (PBMCs) and in an established cell line. In addition, the reverse transcriptase (RT) of many of these clones was expressed and their susceptibility tested in an RT inhibition assay. Nevirapine and efavirenz susceptibilities were tested and compared with a control wild-type virus or RT. RESULTS: Hypersusceptibility to nevirapine and efavirenz was detected using each of the methods described above. R values correlating the other methods with single-cycle assay values were between 0.66 and 0.96. In addition to the high correlations, the different methods gave similar numeric results. CONCLUSIONS: NNRTI hypersusceptibility is readily seen in multicycle susceptibility assays and in enzyme inhibition assays.

Amino Acid Substitution↗
PubMed2005

Impact of HIV-1 subtype and antiretroviral therapy on protease and reverse transcriptase genotype: results of a global collaboration.

BACKGROUND: The genetic differences among HIV-1 subtypes may be critical to clinical management and drug resistance surveillance as antiretroviral treatment is expanded to regions of the world where diverse non-subtype-B viruses predominate. METHODS AND FINDINGS: To assess the impact of HIV-1 subtype and antiretroviral treatment on the distribution of mutations in protease and reverse transcriptase, a binomial response model using subtype and treatment as explanatory variables was used to analyze a large compiled dataset of non-subtype-B HIV-1 sequences. Non-subtype-B sequences from 3,686 persons with well characterized antiretroviral treatment histories were analyzed in comparison to subtype B sequences from 4,769 persons. The non-subtype-B sequences included 461 with subtype A, 1,185 with C, 331 with D, 245 with F, 293 with G, 513 with CRF01_AE, and 618 with CRF02_AG. Each of the 55 known subtype B drug-resistance mutations occurred in at least one non-B isolate, and 44 (80%) of these mutations were significantly associated with antiretroviral treatment in at least one non-B subtype. Conversely, of 67 mutations found to be associated with antiretroviral therapy in at least one non-B subtype, 61 were also associated with antiretroviral therapy in subtype B isolates. CONCLUSION: Global surveillance and genotypic assessment of drug resistance should focus primarily on the known subtype B drug-resistance mutations.

Amino Acid Sequence↗
PubMed2005

T lymphocytes among HIV-infected and -uninfected infants: CD4/CD8 ratio as a potential tool in diagnosis of infection in infants under the age of 2 years.

BACKGROUND: Serologic tests for HIV infection in infants less than 18 months do not differentiate exposure and infection since maternally acquired IgG antibodies may be detected in infants. Thus, the gold standard for diagnosis of HIV-1 infection in infants under the age of 2 years is DNA or reverse transcriptase polymerase chain reaction. There is an urgent need to evaluate alternative and cost effective laboratory methods for early diagnosis of infant HIV-1 infection as well as identifying infected infants who may benefit from cotrimoxazole prophylaxis and/or initiation of highly active antiretroviral therapy. METHODS: Whole blood was collected in EDTA from 137 infants aged 0 to 18 months. DNA polymerase chain reaction was used as the reference standard for diagnosis of HIV-1 infection. T-cell subset profiles were determined by flow cytometry. RESULTS: Seventy-six infants were DNA PCR positive while 61 were negative. The median CD4 counts of PCR negative infants were significantly higher than those of the PCR positive infants, p < 0.001. The median CD4/CD8 ratio and the %CD4 of the PCR positive infants were both significantly lower than those of the negative infants, p < 0.001. The CD4/CD8 ratio had a >98% sensitivity for diagnosis of HIV-1 infection and a specificity of >98%. CONCLUSION: The CD4/CD8 ratio appears useful in identifying HIV-infected infants. The development of lower cost and more robust flow cytometric methods that provide both CD4/CD8 ratio and %CD4 may be cost-effective for HIV-1 diagnosis and identification of infants for cotrimoxazole prophylaxis and/or highly active antiretroviral therapy.

Journal Article↗
PubMed2005

The feasibility of voluntary counselling and HIV testing for pregnant women using community volunteers in Zimbabwe.

The purpose of this pilot project was to assess the feasibility and acceptability of voluntary counselling and HIV testing (VCT) by pregnant women using community volunteers in Zimbabwe to prevent mother to child transmission (MTCT) of HIV. From July 1999 to June 2001, a short-course zidovudine (ZDV)-based perinatal HIV prevention programme was initiated in two antenatal clinics. Community volunteers, recruited from local community organizations, underwent a two-week training course in VCT, which included HIV/AIDS facts, systematic counselling approach, and practical counselling techniques using scripts and role-play. Rapid HIV testing was performed after informed consent. Lay counsellors conducted individual pre- and post-test counselling for HIV. A total of 35 women community volunteers were trained in VCT; 34 graduated and committed to work four hours per week in the clinic. Of the 6051 pregnant women presenting for antenatal clinics (ANC), 1824 (30%) underwent pre-test counselling and 1547 (26%) were tested, and 429 (28%) were HIV infected. Overall, 1283 (83%) returned for their test results including 406 (95%) of HIV-infected women. Of the 406 HIV-infected women who collected their test results, only 203 (50%) opted for ZDV prophylaxis to prevent MTCT of HIV. Over the two-year study period, two counsellors died and three sought employment at other organizations. Adherence to duty roster was 97% and no breach of confidentiality was reported. Despite many challenges, VCT delivered by community volunteers is feasible and acceptable for pregnant women aiming to reduce their risk of transmitting HIV to their infants. This programme is being implemented at several urban and rural MTCT sites in Zimbabwe and can serve as a model for other resource-poor countries.

AIDS Serodiagnosis↗
PubMed2004

Genetic correlates of efavirenz hypersusceptibility.

BACKGROUND: Non-nucleoside reverse transcriptase inhibitor (NNRTI) hypersusceptibility is seen in approximately 30% of HIV isolates with nucleoside reverse transcriptase inhibitor (NRTI) resistance. NNRTI hypersusceptibility has been associated with improved outcomes to NNRTI-based therapy. OBJECTIVE: To determine the genetic correlates of efavirenz hypersusceptibility. METHODS: Paired baseline genotypes and phenotypes were obtained from 444 NRTI-experienced, NNRTI-naive patients. Fisher's exact tests, recursive partitioning (classification and regression trees; CART), and stepwise binary regression were used to identify specific reverse transcriptase (RT) mutations associated with efavirenz hypersusceptibility. RESULTS: In univariate analyses, 26 RT codons were associated with efavirenz hypersusceptibility (P < 0.05), the top five were 215 > 41 > 210 > 118 > 208 (all P < 0.000001). From stepwise model selection, the 215, 208 and 118 mutations remained independently predictive of efavirenz hypersusceptibility. A final binary regression model to predict efavirenz hypersusceptibility included one covariate for the 215 mutation (relative risk 2.6, P < 0.0001) and a second covariate representing either the 208 or 118 mutation (relative risk 1.8, P < 0.0001). Similarly, in a CART analysis, a mutation at codon 215 was the first split selected, followed by mutations at 208 and 118. An efavirenz hypersusceptibility genotypic score using the three mutations 208, 118 and 215 was as accurate at predicting efavirenz hypersusceptibility as a more complex scoring system using 26 mutations. CONCLUSION: Mutations at 215, 208 and 118 were independently associated with NNRTI hypersusceptibility. After confirmatory studies using other large datasets, incorporating a hypersusceptibility score into genotype interpretation algorithms will improve the prediction of NNRTI hypersusceptibility.

Alkynes↗
PubMed2004

Treatment for adult HIV infection: 2004 recommendations of the International AIDS Society-USA Panel.

CONTEXT: Substantial changes in the field of human immunodeficiency virus (HIV) treatment have occurred in the last 2 years, prompting revision of the guidelines for antiretroviral management of adults with established HIV infection. OBJECTIVE: To update recommendations for physicians who provide HIV care regarding when to start antiretroviral therapy, what drugs to start with, when to change drug regimens, and what drug regimens to switch to after therapy fails. DATA SOURCES: Evidence was identified and reviewed by a 16-member noncompensated panel of physicians with expertise in HIV-related basic science and clinical research, antiretroviral therapy, and HIV patient care. The panel was designed to have broad US and international representation for areas with adequate access to antiretroviral management. STUDY SELECTION: Evidence considered included published basic science, clinical research, and epidemiological data (identified by experts in the field or extracted through MEDLINE searches using terms relevant to antiretroviral therapy) and abstracts from HIV-oriented scientific conferences between July 2002 and May 2004. DATA EXTRACTION: Data were reviewed to identify any information that might change previous guidelines. Based on panel discussion, guidelines were drafted by a writing committee and discussed by the panel until consensus was reached. DATA SYNTHESIS: Four antiretroviral drugs recently have been made available and have broadened the options for initial and subsequent regimens. New data allow more definitive recommendations for specific drugs or regimens to include or avoid, particularly with regard to initial therapy. Recommendations are rated according to 7 evidence categories, ranging from I (data from prospective randomized clinical trials) to VII (expert opinion of the panel). CONCLUSION: Further insights into the roles of drug toxic effects, drug resistance, and pharmacological interactions have resulted in additional guidance for strategic approaches to antiretroviral management.

Adult↗
PubMed2004

Infant feeding practices of HIV-infected and uninfected women in Zimbabwe.

We surveyed infant feeding knowledge, attitudes, and practices in Zimbabwe to determine whether knowledge of HIV seropositivity influences infant feeding behavior. Questionnaires were administered to 97 women 1 and 4 weeks postpartum and prospective data on infant feeding practices were collected. Participants were pregnant women who consented to a HIV test. A total of 116 women participated of whom 99 women underwent voluntary HIV counseling and testing (VCT); 17 women agreed to blinded HIV testing but did not opt for VCT. The responses to questionnaires on infant feeding practices of HIV-positive and HIV-negative women who knew and did not know their HIV status at day 1 and week 4 postpartum were compared. We found that HIV-positive women who did not learn their status breastfed their infants less, introduced supplementary foods sooner, and planned to wean their babies earlier compared to other women (p = 0.005, p = NS, p= 0.02). HIV-positive women (30/97) more frequently reported a prior history of infant death and AIDS-related symptoms compared to HIV-negative women. We conclude that HIV-positive women who did not know their status made incorrect decisions with respect to infant feeding. These women may have suspected themselves to be HIV-positive and consequently underfed their infants or because these women were more symptomatic may have been less likely to breastfeed; decreased intake may increase the risk for malnutrition. Knowledge of HIV status may influence infant feeding decisions and reveal an urgent need to address infant feeding practices of pregnant women in Zimbabwe.

Adult↗
PubMed2003

Safety and trough concentrations of nevirapine prophylaxis given daily, twice weekly, or weekly in breast-feeding infants from birth to 6 months.

Despite the success of antiretroviral prophylaxis in reducing mother-to-child HIV-1 transmission, postpartum transmission through breast milk remains a problem. Antiretroviral administration to the infant during the period of breast-feeding could protect against postnatal transmission. An open-label phase 1/2 study was designed to assess the safety and trough concentrations of nevirapine (NVP) given once weekly (OW), twice weekly (TW), or once daily (OD) to HIV-exposed breast-feeding infants for 24 weeks. Following maternal dosing with 200 mg NVP orally at onset of labor, breast-feeding infants were randomized within 48 hours of birth to 1 of 3 regimens: arm 1, NVP given OW (4 mg/kg from birth to 14 days, upward arrow to 8 mg/kg from 15 days to 24 weeks), arm 2, NVP given TW (4 mg/kg from birth to 14 days, upward arrow to 8 mg/kg from 15 days to 24 weeks), and arm 3, NVP given OD (2 mg/kg from birth to 14 days, upward arrow to 4 mg/kg from 15 days to 24 weeks). Trough NVP concentrations and clinical and laboratory abnormalities were monitored. Of the 75 infants randomized (26 to OW, 25 to TW, and 24 to OD dosing), 63 completed the 32-week follow-up visit. No severe skin, hepatic, or renal toxicity related to NVP was observed. Neutropenia occurred in 8 infants. Trough NVP levels were lower than the therapeutic target (100 ng/mL) in 48 of 75 (64.0%) samples from infants in the OW arm, 3 of 65 (4.6%) samples in the TW arm, and 0 of 72 samples in the OD arm. Median (range) trough NVP concentrations were 64 ng/mL (range: <25-1519 ng/mL) with OW dosing; 459 (range: <25-1386 ng/mL) with TW dosing; and 1348 (range: 108-4843 ng/ml) with OD dosing. Our data indicate that NVP prophylaxis for 6 months was safe and well tolerated in infants. OD NVP dosing resulted in all infants with trough concentration greater than the therapeutic target and maintenance of high drug concentrations. A phase 3 study is planned to assess the efficacy of OD infant NVP regimen to prevent breast-feeding HIV-1 transmission.

Acquired Immunodeficiency Syndrome↗
PubMed2003

Clinical impact of the M184V mutation on switching to didanosine or maintaining lamivudine treatment in nucleoside reverse-transcriptase inhibitor-experienced patients.

Virologic outcome among 104 lamivudine (3TC)-experienced individuals infected with human immunodeficiency virus type 1 who switched to a didanosine (ddI)-containing triple- or quadruple-drug regimen was compared with those who continued receiving a 3TC-containing regimen. A significantly increased independent risk of virologic failure was associated with continuing a 3TC-containing regimen. In addition, most patients for whom the ddI-containing regimen failed lost the M184V/I mutation. These results show that ddI continues to provide activity against viruses with the M184V/I mutation and suggest that the presence of the M184V/I mutation should not preclude the use of ddI in nucleoside-experienced patients.

Anti-HIV Agents↗
PubMed2003

Phenotypic susceptibility and virological outcome in nucleoside-experienced patients receiving three or four antiretroviral drugs.

OBJECTIVE: To evaluate phenotypic drug susceptibility and non-nucleoside reverse transcriptase inhibitor hypersusceptibility as predictors of the time to virological failure. DESIGN: In a randomized clinical trial, phenotypic susceptibility was retrospectively determined among 131 exclusively nucleoside reverse transcriptase inhibitor (NRTI)-experienced patients with baseline HIV-RNA levels greater than 2000 copies/ml. Subjects were assigned two NRTI drugs and were randomly assigned to nelfinavir, efavirenz, or both. Virological failure was defined as two HIV-RNA measurements of 2000 copies/ml or greater at or after week 16 and before treatment discontinuation. METHODS: Using biological cut-offs to define resistance, assigned NRTI and randomized drug regimens, continuous and dichotomous phenotypic susceptibility scores (PSS) were calculated for each virus. Efavirenz hypersusceptibility as a dichotomous value was defined as less than 0.4-fold resistance. Associations between virological failure and continuous and dichotomous PSS were evaluated using Kaplan-Meier curves and Cox proportional hazards regression models. RESULTS: A higher baseline viral load (P < 0.02) and lower dichotomous or continuous baseline PSS (P = 0.004 and P < 0.001, respectively) were independently associated with virological failure. In the 85 subjects who received efavirenz, efavirenz hypersusceptibility (P = 0.042, hazard ratio 0.43, 95% confidence interval 0.19-0.97) was independently associated with a reduced risk of virological failure. CONCLUSION: Reduced phenotypic susceptibility was a significant independent risk factor for virological failure. The presence of efavirenz hypersusceptibility appeared to enhance virological responses during treatment with efavirenz in combination with NRTIs. The retrospective calculation of continuous PSS accurately identified treatment regimens containing sufficient drug activity to prevent virological failure.

Alkynes↗
PubMed2003

High frequency of syncytium-inducing and CXCR4-tropic viruses among human immunodeficiency virus type 1 subtype C-infected patients receiving antiretroviral treatment.

Human immunodeficiency virus type 1 (HIV-1) subtype C viruses have been found to almost exclusively use the chemokine receptor CCR5 as a coreceptor for entry, even in patients with advanced AIDS. We have characterized subtype C virus isolates from 28 patients from Harare, Zimbabwe, 20 of whom were receiving antiretroviral treatment. Virus from 10 of the treated patients induced syncytium formation (SI virus) when cultured with MT2 cells. Only non-syncytium-inducing (NSI) virus was cultured from the peripheral blood mononuclear cells of the eight patients who had not received treatment. The majority of these subtype C SI viruses were capable of using both CCR5 and CXCR4 as coreceptors for viral entry, and the consensus V3 loop sequences from the SI viruses displayed a high net charge compared to those of NSI viruses. While those on treatment had reverse transcriptase (RT) and protease mutations, there was no clear association between RT and protease drug resistance mutations and coreceptor tropism. These results suggest that CXCR4-tropic viruses are present within the quasispecies of patients infected with subtype C virus and that antiretroviral treatment may create an environment for the emergence of CXCR4 tropism.

Amino Acid Sequence↗