Drug resistance after failure of initial antiretroviral therapy in resource-limited countries.
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Developing Countries↗
Biomedical subjects
Joel E Gallant
Publications and source records attributed to Joel E Gallant.
Tenofovir disoproxil fumarate, emtricitabine, and efavirenz versus fixed-dose zidovudine/lamivudine and efavirenz in antiretroviral-naive patients: virologic, immunologic, and morphologic changes--a 96-week analysis.
BACKGROUND: In antiretroviral-naive patients, tenofovir disoproxil fumarate (TDF), emtricitabine (FTC), and efavirenz (EFV) demonstrated superior outcomes compared with fixed-dose zidovudine (ZDV)/lamivudine (3TC) and EFV through 48 weeks. Results through a 96-week extension phase are presented. METHODS: In this randomized, open-label, noninferiority trial, 517 antiretroviral-naive HIV-infected patients received TDF, FTC, and EFV (TDF + FTC + EFV) or ZDV/3TC and EFV (ZDV/3TC + EFV). The primary endpoint was the proportion of patients with an HIV RNA level <400 copies/mL in patients without baseline nonnucleoside resistance. RESULTS: Through week 96, significantly more patients receiving TDF + FTC + EFV achieved and maintained an HIV RNA level <400 copies/mL (75% receiving TDF + FTC + EFV vs. 62% receiving ZDV/3TC + EFV; P = 0.004). There was a trend toward greater virologic suppression to <50 copies/mL in the TDF + FTC + EFV group (67% vs. 61%; P = 0.16). The TDF + FTC + EFV group demonstrated a significantly greater increase in CD4 count (270 vs. 237 cells/mm; P = 0.036). No patient developed the K65R mutation. Limb fat at week 96 was significantly greater in the TDF + FTC + EFV group versus the ZDV/3TC + EFV group (7.7 vs. 5.5 kg; P < 0.001). CONCLUSION: Over 96 weeks, the combination of TDF, FTC, and EFV was superior to fixed-dose ZDV/3TC + EFV for achieving and maintaining an HIV RNA level <400 copies/mL and an increase in CD4 cells.
Adenine↗
Antiretroviral therapy in the treatment of HIV-associated nephropathy.
BACKGROUND: The effect of antiretroviral therapy (ART) on the clinical course of patients with human immunodeficiency virus (HIV)-associated nephropathy (HIVAN) is not well-established. This study was undertaken to further elucidate the potential benefit of ART in HIV-infected patients with documented HIVAN. METHODS: A cohort of 263 consecutive HIV-infected patients referred to the Johns Hopkins renal clinic from 1995 to 2004 was examined. Patients were included if they had biopsy-proven HIVAN and did not require dialysis within 1 month of their kidney biopsy. The cumulative probability of renal survival was calculated using the Kaplan-Meier method. Multivariate analysis was performed using the Cox regression method. RESULTS: Fifty-three patients among 152 biopsied patients had HIVAN. Among 36 patients who met the inclusion criteria, 26 were treated with ART (group I) and 10 patients were not (group II). Except for age, baseline demographics and clinical characteristics were similar in the two groups. Renal survival was significantly better in the group receiving ART by both univariate (P = 0.025) and multivariate analysis (overall adjusted hazard ratio = 0.30; 95% confidence interval 0.09-0.98; P < 0.05) for ART compared with no treatment. CONCLUSIONS: Patients with biopsy-proven HIVAN treated with ART had better renal survival compared with patients who did not receive ART. HIVAN should be considered as an indication to initiate ART.
AIDS-Associated Nephropathy↗
HIV type 1 RNA level as a clinical indicator of renal pathology in HIV-infected patients.
To determine the value of human immunodeficiency virus type 1 (HIV-1) RNA level in distinguishing HIV-associated nephropathy from non-HIV-associated nephropathy renal pathological conditions, we retrospectively compared renal histopathological findings for 86 HIV-infected patients according to HIV-1 RNA levels. We found that HIV-associated nephropathy was unlikely among patients with HIV-1 RNA levels <400 copies/mL. Hypertensive vascular disease surpassed HIV-associated nephropathy as the most common renal pathological finding among the entire cohort. HIV-1 RNA level did not correlate with renal survival.
AIDS-Associated Nephropathy↗
Marked intraindividual variability in antiretroviral concentrations may limit the utility of therapeutic drug monitoring.
BACKGROUND: Effective therapeutic drug monitoring for antiretrovirals requires a better understanding of intraindividual variability in pharmacokinetics. METHODS: We determined concentrations of human immunodeficiency virus (HIV) protease and nonnucleoside reverse-transcriptase inhibitors for 10 patients with undetectable plasma HIV RNA levels who had been receiving stable regimens for > or = 11 months. Plasma samples were collected at the same time of day 3 times per week for up to 4 months. Patients were instructed to take their antiretrovirals at the same time every day. Plasma protease and nonnucleoside reverse-transcriptase inhibitor concentrations were determined using high-performance liquid chromatographic methods. Pharmacokinetic variability was expressed as intraindividual percentage coefficient of variation (ICV), which was calculated as the patient's standard deviation divided by the mean drug concentration for that patient. RESULTS: ICV was determined for 6 drugs for 10 patients, for a total of 17 different patient-drug combinations, using 600 total samples. ICV was unexpectedly high for most patients who were receiving protease inhibitors (ICVs for individual patients taking lopinavir/ritonavir were 24%, 33%, 51%, and 92%; for patients taking nelfinavir/M8 metabolite, they were 30%/44% and 39%/54%; for patients taking ritonavir, they were 34% and 43%; for patients taking saquinavir, they were 52% and 55%). ICVs for patients receiving nonnucleoside reverse-transcriptase inhibitors were lower (for patients receiving efavirenz, they were 7%, 13%, 29%, and 51%; for a patient receiving nevirapine, it was 25%). The median ICV for all patients receiving protease inhibitors (n = 12) was 43.5%, and for all patients receiving nonnucleoside reverse-transcriptase inhibitors (n = 5), the median ICV was 25%. CONCLUSIONS: Intraindividual variability in concentrations of antiretrovirals was surprisingly high in virologically suppressed patients. Possible contributors include food effects, concomitant use of prescription and herbal medications, assay variability, or medication timing, which was assessed by self-report. High intraindividual pharmacokinetic variability may limit the utility of single measurements in therapeutic drug monitoring for some antiretroviral agents.
Acquired Immunodeficiency Syndrome↗
Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV.
BACKGROUND: Durable suppression of replication of the human immunodeficiency virus (HIV) depends on the use of potent, well-tolerated antiretroviral regimens to which patients can easily adhere. METHODS: We conducted an open-label, noninferiority study involving 517 patients with HIV infection who had not previously received antiretroviral therapy and who were randomly assigned to receive either a regimen of tenofovir disoproxil fumarate (DF), emtricitabine, and efavirenz once daily (tenofovir-emtricitabine group) or a regimen of fixed-dose zidovudine and lamivudine twice daily plus efavirenz once daily (zidovudine-lamivudine group). The primary end point was the proportion of patients without baseline resistance to efavirenz in whom the HIV RNA level was less than 400 copies per milliliter at week 48 of the study. RESULTS: Through week 48, significantly more patients in the tenofovir-emtricitabine group reached and maintained the primary end point of less than 400 copies of HIV RNA per milliliter than did those in the zidovudine-lamivudine group (84 percent vs. 73 percent, respectively; 95 percent confidence interval for the difference, 4 to 19 percent; P=0.002). This difference excludes the inferiority of the tenofovir DF, emtricitabine, and efavirenz regimen, indicating a significantly greater response with this regimen. Significant differences were also seen in the proportion of patients with HIV RNA levels of less than 50 copies per milliliter (80 percent in the tenofovir-emtricitabine group vs. 70 percent in the zidovudine-lamivudine group; 95 percent confidence interval for the difference, 2 to 17 percent; P=0.02) and in increases in CD4 cell counts (190 vs. 158 cells per cubic millimeter, respectively; 95 percent confidence interval for the difference, 9 to 55; P=0.002). More patients in the zidovudine-lamivudine group than in the tenofovir-emtricitabine group had adverse events resulting in discontinuation of the study drugs (9 percent vs. 4 percent, respectively; P=0.02). In none of the patients did the K65R mutation develop. CONCLUSIONS: Through week 48, the combination of tenofovir DF and emtricitabine plus efavirenz fulfilled the criteria for noninferiority to a fixed dose of zidovudine and lamivudine plus efavirenz and proved superior in terms of virologic suppression, CD4 response, and adverse events resulting in discontinuation of the study drugs. (ClinicalTrials.gov number, NCT00112047.)
Adenine↗
Risk factors for human herpesvirus 8 seropositivity in the AIDS Cancer Cohort Study.
BACKGROUND: Cigarette smoking has been associated with a decreased risk for AIDS-related and classical KS, but whether it is associated with decreased risk of human herpesvirus 8 (HHV-8) infection is unknown. STUDY DESIGN: We evaluated factors associated with HHV-8 seropositivity in 2795 participants (132 with KS) in the National Cancer Institute AIDS Cancer Cohort, including 1621 men who have sex with men (MSM), 660 heterosexual men and 514 women. Odds ratios (OR) and 95% confidence intervals were estimated using logistic regression models. RESULTS: Among non-KS subjects, HHV-8 seropositivity was 6%, 13% and 29% among women, heterosexual men and MSM, respectively. HHV-8 seropositivity was decreased in heavier (> or =1/2 pack/day) compared to lighter smokers among women (5% versus 8%; adjusted OR (aOR) 0.4; 95% CI 0.2-0.8) and MSM (27% versus 32%; aOR 0.7; 95% CI 0.6-1.0), but not among heterosexual men (12% versus 16%; aOR 0.7; 95% CI 0.4-1.2). HHV-8 seroprevalence was increased in heavier (> or =1 drink/day) compared to lighter consumers of alcohol among women (16% versus 4%; adjusted OR 5.2; 95% CI 2.3-12), but not among MSM (33% versus 28%; aOR 1.2; 95% CI 0.9-1.6) or heterosexual men (13% versus 13%; aOR 1.1; 95% CI 0.6-2.0). In analyses adjusted for smoking and drinking, HHV-8 seropositivity was positively associated with chlamydia infection (OR=4.3; 95% CI 1.2-13) and with marital status among women p(heterogeneity)=0.03, and with hepatitis (OR=1.6; 95% CI 1.2-2.1), gonorrhea (OR=1.5; 95% CI 1.1-1.9), genital warts (OR=1.5; 95% CI 1.1-2.0) and nitrate inhalant use (OR=1.7; 95% CI 1.3-2.3) among MSM. CONCLUSIONS: Inverse association of HHV-8 seropositivity with cigarette smoking may indicate protective effect of tobacco smoke on HHV-8 infection, whereas positive associations with alcohol may reflect either behavioral factors or biological effects modulating susceptibility. Smoking and drinking may influence KS risk, at least in part, by altering the natural history of HHV-8 infection.
AIDS-Related Opportunistic Infections↗
Residual human immunodeficiency virus type 1 viremia in some patients on antiretroviral therapy is dominated by a small number of invariant clones rarely found in circulating CD4+ T cells.
Antiretroviral therapy can reduce human immunodeficiency virus type 1 (HIV-1) viremia to below the detection limit of ultrasensitive clinical assays (50 copies of HIV-1 RNA/ml). However, latent HIV-1 persists in resting CD4+ T cells, and low residual levels of free virus are found in the plasma. Limited characterization of this residual viremia has been done because of the low number of virions per sample. Using intensive sampling, we analyzed residual viremia and compared these viruses to latent proviruses in resting CD4+ T cells in peripheral blood. For each patient, we found some viruses in the plasma that were identical to viruses in resting CD4+ T cells by pol gene sequencing. However, in a majority of patients, the most common viruses in the plasma were rarely found in resting CD4+ T cells even when the resting cell compartment was analyzed with assays that detect replication-competent viruses. Despite the large diversity of pol sequences in resting CD4+ T cells, the residual viremia was dominated by a homogeneous population of viruses with identical pol sequences. In the most extensively studied case, a predominant plasma sequence was also found in analysis of the env gene, and linkage by long-distance reverse transcriptase PCR established that these predominant plasma sequences represented a single predominant plasma virus clone. The predominant plasma clones were released for months to years without evident sequence change. Thus, in some patients on antiretroviral therapy, the major mechanism for residual viremia involves prolonged production of a small number of viral clones without evident evolution, possibly by cells other than circulating CD4+ T cells. The sequences have been deposited in GenBank. The accession numbers are DQ 391282 to DQ 391351 (for env) and DQ 391352 to DQ 392955 (for RT).
Antiretroviral Therapy, Highly Active↗
Bimodal virological response to antiretroviral therapy for HIV infection: an application using a mixture model with left censoring.
STUDY OBJECTIVE: To assess whether HIV RNA levels (log(10) scale) in highly active antiretroviral therapy (HAART) treated population have a bimodal distribution, suggesting optimal or suboptimal response to HAART. METHODS: The study population from two ongoing cohort studies comprised 564 men (4785 person visits) and 1173 women (8675 person visits) with known dates of HAART initiation and with HIV RNA measurements before and after initiation. Values below detection limit of assays were treated in the analysis as left censored. Maximum likelihood methods were used to estimate parameters and to determine possible bimodality of HIV RNA distributions. RESULTS: A two component mixture model fitted HIV RNA levels significantly better than did a single component distribution at different years from HAART initiation in both therapy experienced and therapy naive patients. In the fifth year after HAART initiation, 32% of men and 44% of women had HIV RNA in the higher component with medians of 5247 and 9253 copies/ml, respectively, suggesting suboptimal virological response to HAART, which was associated with poor adherence and lower frequency of CCR5 heterozygous genotype. CONCLUSION: The bimodal distribution of HIV RNA persisted during the years after HAART initiation. The high occurrence of suboptimal virological response at the fifth year after HAART initiation underscore the needs for careful monitoring and patient education about the importance of treatment adherence. This data analysis overcomes limitations of measurement techniques of observations having values below detection limits and serves to characterise the dynamics of the virological response to therapies.
Adult↗
Tenofovir disoproxil fumarate for the treatment of HIV infection.
Tenofovir disoproxil fumarate is a nucleotide analogue reverse transcriptase inhibitor approved by the FDA for the treatment of HIV infection. It is a potent agent with a long intracellular half-life that allows for once-daily dosing. It has been well tolerated in clinical trials, without evidence of the mitochondrial toxicity that has been associated with long-term treatment of some of the nucleoside analogue reverse transcriptase inhibitors. Because of its demonstrated efficacy and favourable safety profile, tenofovir disoproxil fumarate has quickly become a favoured nucleoside component of antiretroviral regimens for both treatment-naive and -experienced patients.
Adenine↗
High frequency of highly active antiretroviral therapy modifications in patients with acute or early human immunodeficiency virus infection.
STUDY OBJECTIVES: To examine the frequency of highly active antiretroviral therapy (HAART) modifications, the reasons for these modifications, and toxicities of these drugs in patients receiving their first HAART regimen after a diagnosis of acute (< 2 mo from infection) or early (2-12 mo) human immunodeficiency virus (HIV) infection. PATIENTS: Fifty-one patients who were enrolled in the Acute Infection and Early Disease Research Program at a Baltimore, Maryland, site between January 1, 1998, and April 30, 2002, and who chose to start HAART. MEASUREMENTS AND MAIN RESULTS: Time from initiation of therapy to first modification-defined as change in any HAART drug without an interruption in therapy or as simultaneous discontinuation of all drugs within the regimen-and time from initiation of therapy to reinitiation of therapy were recorded, as well as reasons for modification and reinitiation. With a median follow-up of 1,549 days, 21 (41%) of 51 patients received HAART continuously, but only 10 (20%) continued to receive their original regimen without any modification. Among the 41 patients (80%) who received modified therapy, the main reasons for the first modification were toxicity (16 patients), nonadherence (8), and new data on treatment efficacy or safety (8). Of 30 patients who stopped HAART, 18 restarted HAART at a later time. CONCLUSION: The high frequency of treatment modification among patients treated after acute or early HIV infection underscores the importance of determining the usefulness of antiretroviral therapy early in HIV infection, and the need for more tolerable regimens if HAART is to be started at this stage.
Acute Disease↗
Antiretroviral news from the 45th ICAAC.
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Anti-HIV Agents↗
Antiretroviral news from the 10th EACS, Dublin.
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Anti-HIV Agents↗
Editorial comment: treating the experienced patient--when and how to use new agents.
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Anti-HIV Agents↗
Editorial comment: predictors of response--updating the traditional list.
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Anti-Retroviral Agents↗
The M184V mutation: what it does, how to prevent it, and what to do with it when it's there.
The M184V mutation is selected by lamivudine (3TC) and emtricitabine (FTC) and is a common mutation in HIV-infected patients. Virus with the M184V mutation has a high level of resistance to 3TC and FTC but has been shown to have favorable effects on the susceptibility of some other NRTIs and can delay clinical and immunologic progression by decreasing viral fitness. While it is always better not to have any drug resistance so that 3TC and FTC are available as active antiretroviral agents, it is important to take advantage of the beneficial effects of the M184V mutation when it is present.
Anti-HIV Agents↗
Early virologic nonresponse to tenofovir, abacavir, and lamivudine in HIV-infected antiretroviral-naive subjects.
BACKGROUND: Antiretroviral combinations that reduce the number of pills and dosing frequency have the potential to simplify therapy. We compared 2 regimens dosed as 2 pills once daily. METHODS: This was a randomized, open-label, multicenter study of tenofovir disoproxil fumarate versus efavirenz, both administered once daily with the abacavir/lamivudine fixed-dose combination in treatment-naive human immunodeficiency virus type 1 (HIV-1)-infected subjects. After reports of early nonresponse, an unplanned interim analysis was performed. Virologic nonresponse was defined as (1) a <2.0-log(10) copies/mL decrease in HIV-1 RNA level by week 8, (2) an HIV-1 RNA rebound of > or =1.0 log(10) copies/mL above the nadir, or (3) for subjects with 2 consecutive HIV-1 RNA measurements <50 copies/mL, a subsequent increase to >400 copies/mL on 2 consecutive occasions. RESULTS: We randomized 340 subjects. Median baseline HIV-1 RNA level and CD4+ cell count were 4.7 log(10) copies/mL and 251 cells/mm3, respectively; 194 subjects with HIV-1 RNA data from > or =8 weeks were included in the interim analysis. Virologic nonresponse occurred in 50 (49%) of 102 subjects in the tenofovir disoproxil fumarate arm, compared with 5 (5%) of 92 of subjects in the efavirenz arm (P<.001). Within 12 weeks, viral genotypes for nonresponders in the tenofovir disoproxil fumarate arm showed M184V or I/M/V mixtures in 40 (98%) of 41 subjects and K65R and M184V or mixtures in 22 (54%) of 41 subjects. The protocol was immediately amended to modify the tenofovir disoproxil fumarate arm. The efavirenz arm continued unchanged; after 48 weeks, 120 (71%) of 169 subjects achieved HIV-1 RNA levels <50 copies/mL. CONCLUSION: The tenofovir disoproxil fumarate/abacavir/lamivudine regimen resulted in an unexpected and unacceptably high rate of nonresponse and incidence of K65R and M184V/I. This 3-drug regimen should not be used.
Adenine↗
Risk factors for Kaposi's sarcoma among HHV-8 seropositive homosexual men with AIDS.
Kaposi's sarcoma (KS) is a frequent complication of the acquired immunodeficiency syndrome (AIDS) in homosexual men. Risk factors for developing this malignancy are uncertain, other than immunosuppression and coinfection with human herpesvirus 8 (HHV-8). We therefore examined factors associated with KS in a cross-sectional analysis of 99 cases among 503 HHV-8 seropositive homosexual men with AIDS. Data were collected by computer-assisted personal interviews and medical chart reviews. HHV-8 seroreactivity was determined by enzyme-linked immunosorbent assay for antibodies against HHV-8 K8.1 glycoprotein. KS was significantly less common in blacks compared to whites [risk ratio (RR) = 0.4; 95% CI = 0.2 =0.8] and more common in subjects who had completed college (RR = 1.7; 95% CI = 1.1-2.7) or had annual income greater than dollar 30,000 (RR = 1.5; 95% CI = 1.1-2.2). KS was less common in cigarette smokers (RR = 0.6; 95% CI = 0.5-0.9) and users of crack cocaine (RR = 0.4; 95% CI = 0.1-0.8). KS was less common in bisexual men compared to men who were exclusively homosexual (estimated RR = 0.6; 95% CI = 0.4-0.9) and inversely associated with number of female partners. KS was also less common in men who had received pay for sex (RR = 0.6; 95% CI = 0.4-1.0). These cross-sectional associations could be biased by potential differences in relative timing of HHV-8 and HIV infection, a postulated determinant of KS risk. Alternatively, our findings may reflect factors protective against KS in individuals infected with HHV-8. Future research should focus on identifying practical measures for countering KS that do not increase the risk of other diseases.
Acquired Immunodeficiency Syndrome↗