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PubMed1999

A simple relationship between viral load and survival time in HIV-1 infection.

Despite important recent insights into the short-term dynamics of HIV-1 infection, our understanding of the long-term pathogenesis of AIDS remains unclear. Using an approach that places rapid progressors, typical progressors, and nonprogressors on a single clinical spectrum of disease progression, we quantitate the previously reported relationship between viral load and survival time. We introduce the concept of viral constant, present evidence that this quantity is conserved across patients, and explore the immunopathological implications of this finding. We conclude with a quantitative approach for assessing the benefits of a given regime of antiviral therapy.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Human papillomavirus viral load: a possible marker for cervical disease in HIV-infected women.

Laboratory markers of human papillomavirus infection have been recognized as relevant tools in programmes designed to reduce the burden of cervical cancer. The ongoing experience with these laboratory markers serves to confirm not only their negative predictive value (close to 100%) but also their positive association with developing or developed lesions. This aspect is particularly relevant in HIV-infected subjects who show an increased prevalence, incidence and severity of infections and lesions even in the era of efficacious control of their immunosuppression. Among the possible virus-related parameters proposed as relevant markers (viral persistence, load, expression, genomic integration capacity) we here analyse the informative value of human papillomavirus viral load measurement as a possible risk marker in this particular clinical setting.

Biomarkers↗

PubMed2000

Analysis of left-censored longitudinal data with application to viral load in HIV infection.

The classical model for the analysis of progression of markers in HIV-infected patients is the mixed effects linear model. However, longitudinal studies of viral load are complicated by left censoring of the measures due to a lower quantification limit. We propose a full likelihood approach to estimate parameters from the linear mixed effects model for left-censored Gaussian data. For each subject, the contribution to the likelihood is the product of the density for the vector of the completely observed outcome and of the conditional distribution function of the vector of the censored outcome, given the observed outcomes. Values of the distribution function were computed by numerical integration. The maximization is performed by a combination of the Simplex algorithm and the Marquardt algorithm. Subject-specific deviations and random effects are estimated by modified empirical Bayes replacing censored measures by their conditional expectations given the data. A simulation study showed that the proposed estimators are less biased than those obtained by imputing the quantification limit to censored data. Moreover, for models with complex covariance structures, they are less biased than Monte Carlo expectation maximization (MCEM) estimators developed by Hughes (1999) Mixed effects models with censored data with application to HIV RNA Levels. Biometrics 55, 625-629. The method was then applied to the data of the ALBI-ANRS 070 clinical trial for which HIV-1 RNA levels were measured with an ultrasensitive assay (quantification limit 50 copies/ml). Using the proposed method, estimates obtained with data artificially censored at 500 copies/ml were close to those obtained with the real data set.

Journal Article↗

PubMed1996

Kinetics of appearance of neutralizing antibodies in 12 patients with primary or recent HIV-1 infection and relationship with plasma and cellular viral loads.

HIV-1 primary infection is characterized by a short high titer viremia, which rapidly declines as the immune response emerges. The role of autologous neutralizing antibodies in the decline of viral replication was evaluated in 12 patients with primary or recent HIV-1 infection. Neutralizing antibodies detected for each patient could not generally be observed before several months after isolation of the first obtained HIV isolate. The plasma viral load, as measured by quantitation of the HIV-1 RNA, underwent a global decrease during the first 6 months of the infection, but this decrease did not seem to be associated with the emergence of neutralizing antibodies. The proviral load in peripheral blood mononuclear cells, which was studied by quantitative DNA polymerase chain reaction, exhibited fluctuations and was not as well curtailed as the plasma viremia in the majority of patients.

Adult↗

PubMed1993

High viral load in lymph nodes and latent human immunodeficiency virus (HIV) in peripheral blood cells of HIV-1-infected chimpanzees.

We have examined human immunodeficiency virus type 1 (HIV-1) infection in chimpanzees by analyzing HIV-1 DNA and RNA in lymph nodes and peripheral mononuclear cells (PBMCs). Like certain asymptomatic HIV-infected persons, these chimpanzees had no detectable viral replication in their PBMCs. However, viral replication and a high viral load were observed in the lymphatic tissue. Despite the absence of viral replication in PBMCs, 1/1,000 to 1/10,000 of the PBMCs contained HIV-1 proviral DNA, and HIV transcription could be rapidly induced in these cells in vitro. These results provide direct evidence of cellular latency of HIV in vivo and suggest that HIV infection in chimpanzees may be a useful model for clinical latency of HIV infection in humans.

Animals↗

PubMed1997

Reductions in viral load and increases in T lymphocyte numbers in treatment-naive patients with advanced HIV-1 infection treated with ritonavir, zidovudine and zalcitabine triple therapy.

In order to test the hypothesis that a combination of protease inhibitors with nucleoside analogues-agents known to inhibit different steps of the human immunodeficiency virus (HIV) life cycle--is likely to prove more effective in reducing viral loads than either of those modalities alone, we performed a 60 week, open-label trial in 32 HIV-positive patients with depressed CD4 T lymphocyte cell counts but no active AIDS-defining illnesses. For the first 2 weeks, patients received 600 mg twice daily of liquid ritonavir, a protease inhibitor; then zidovudine 200 mg three times daily and zalcitabine 0.75 mg three times daily were added to the treatment regimen. Mononuclear blood cell fractions were analysed for infected cell levels, using a co-culture system. HIV-1 RNA in plasma was measured both by reverse transcriptase-polymerase chain reaction (RT-PCR) and reverse transcriptase quantitative PCR (QcRT-PCR); lymphocyte counts were determined by standard laboratory methods. In the 2 weeks of ritonavir therapy, both the mean count of infectious blood cells and plasma HIV RNA levels decreased dramatically. Mean CD4 cell counts increased from 173 cells/mm3 at baseline to 286 cells/mm3; CD8 cell counts rose from 951 cells/mm3 to 1,141 cells/mm3. With the introduction of the nucleoside analogues, infectious cell counts and plasma virus dropped another log unit to a nadir at 8 weeks, while CD4 T lymphocyte counts continued to rise slowly. By week 28, 12 patients had withdrawn due to adverse events, none of which were life-threatening. At week 36, infectious material could not be detected in the cells of 10 of the 17 remaining patients; by week 60, four of the seven patients with residual viraemia at week 24 had undergone viral relapse. After the introduction of a more palatable capsule formulation of ritonavir at week 52, infectious cells and plasma virus were undetectable in 50-60% of patients. The combination of protease inhibitors and nucleoside analogues significantly reduces HIV load, and in some patients may suppress viral activity for sustained periods.

Acquired Immunodeficiency Syndrome↗

PubMed2001

Dynamics of viral load in plasma and HIV DNA in lymphocytes during highly active antiretroviral therapy (HAART): high viral burden in macrophages after 1 year of treatment.

In this study we evaluated the level of HIV RNA in plasma and HIV DNA in peripheral blood cells. Sixteen antiretroviral-experienced HIV patients with severe immune suppression were included in the study. After the first month, 56.2% of the patients showed undetectable levels of HIV RNA, this percentage remaining stable after 1 year (53.3%). At enrollment, 7 patients (43.7%) with a low CD4+ T cell count (mean 22 per mm3 versus 73) showed HIV DNA levels below the limit of detection (5 copies/10(5)) in lymphocytes. They all subsequently had increased HIV DNA that became detectable between the first and the third month of therapy, associated with an increase of the CD4+ T cell count (mean 22 to 95/mm3); in 4 of these patients this increase was transitory, becoming undetectable again after one year. In 7 out of the 8 patients with detectable HIV DNA at enrollment, the HIV DNA level decreased over time. Seven out of 15 patients at 1 year (46.7%) showed both undetectable levels of HIV RNA in plasma and HIV DNA in lymphocytes (p<0.05); these patients had a higher CD4+ T cell count at baseline (mean 75 versus 25/mm3) and a higher increase (306 versus 177/mm3) after 1 year. PCR-based dilution assay carried out at 1 year showed that all patients had a consistent amount of HIV DNA positive- CD4+ T lymphocytes and macrophages, with higher values in these last cells. The data indicate that a durable reservoir of virus is still present in both lymphocytes and monocytes, even after long-lasting HAART treatment.

Adult↗

PubMed1995

Determination of human immunodeficiency virus RNA in plasma and cellular viral DNA genotypic zidovudine resistance and viral load during zidovudine-didanosine combination therapy.

Eleven human immunodeficiency virus (HIV)-infected subjects on long-term zidovudine (ZDV) therapy had didanosine (ddI) added to their antiretroviral regimen. HIV RNA in plasma was quantitated by branched-DNA signal amplification assay. Peripheral blood mononuclear cell (PBMC) HIV viral DNA was quantitated by PCR. The relative amounts of wild-type (WT) sequence, ddI resistance-associated codon changes (reverse transcriptase [RT] gene codon 65 K-->R [RT K65R], RT 174V, RT I135K/T/V, and RT M184I/V), and ZDV resistance-associated codon change (RT T215Y/F) from HIV RNA in plasma and RT T215Y/F from PBMC viral DNA were determined by differential hybridization of PCR products from 10 of 11 subjects. All subjects had evidence of RT T215Y/F mutation in both RNA in plasma and PBMC DNA at baseline. Subjects with a mixture of WT and RT T215Y/F HIV RNA in plasma at baseline demonstrated a decline in RNA levels in plasma after the addition of ddI. However, after 6 months of ZDV-ddI therapy, WT HIV RNA in plasma was undetectable in all subjects who had demonstrated a mixture at baseline. Subjects with only RT T215Y/F RNA present in plasma at baseline remained so and demonstrated no decline in RNA levels in plasma. In all subjects, no significant changes in PBMC DNA viral load and RT T215Y/F or WT levels were seen. HIV RNA in plasma demonstrated a significantly higher RT T215Y/F mutant/WT ratio than that of PBMC viral DNA, both at baseline and after ZDV-ddI combination therapy in all subjects. No subjects developed mutations associated with ddI resistance at codons 65, 74, 135, and 184 during this study. This study suggests that determination of relative amounts of RT T215Y/F and WT species from HIV RNA in plasma at baseline may be predictive of virologic response during ZDV-ddI combination therapy.

Base Sequence↗

PubMed1994

Quantitation of hepatitis C viral RNA in sera of hemodialysis patients: gender-related differences in viral load.

Hepatitis C virus (HCV) infection is common in hemodialysis patients, as determined by antibody assays and qualitative polymerase chain reaction (PCR) analysis of serum HCV RNA. To further characterize HCV infection in this population, we measured the viral load in infected hemodialysis patients by a quantitative, competitive PCR assay (QC-PCR) for HCV RNA. Hepatitis C virus RNA levels were correlated with serologic, biochemical, and demographic features of a cohort of hemodialysis patients. Sera from 208 hemodialysis patients were screened for HCV RNA (5' conserved region) by reverse transcriptase PCR (RT-PCR) and HCV-specific antibody. Forty-four patients were antibody positive (21%); among these patients, 34 (77%) were HCV RNA positive. No viremic, seronegative patients were identified. Hepatitis C virus RNA levels quantitated by QC-PCR ranged from 3 x 10(5) to 10(8) molecules of HCV RNA/mL. Male patients had significantly higher mean and median HCV RNA levels (10(7) molecules/mL) compared with female patients (3.6 x 10(6) molecules/mL and 3 x 10(6) molecules/mL, respectfully; P = 0.02). No other demographic or clinical feature of this cohort correlated with HCV RNA levels. Intravenous drug abuse was the most frequently identified risk factor (29% of seropositive patients) for infection with HCV in this population. No association between HCV RNA levels and hepatic enzyme levels (alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, alkaline phosphatase) was apparent. Hepatitis C virus infection is highly prevalent in our hemodialysis population, and hemodialysis patients, particularly males, have high levels of HCV in serum.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed2006

Herpes simplex virus type 1 induction of chemokine production is unrelated to viral load in the cornea but not in the nervous system.

Herpes simplex virus type 1 elicits a strong host inflammatory response after corneal infection. The purpose of the current study was to compare the production of chemokines induced by viral infection at sites known to harbor virus after ocular inoculation in order to determine the relationship between viral load and chemokine expression. Using highly resistant IFN-alpha1 transgenic mice whose transgene is under the control of the glial fibrillary acidic protein promoter in comparison with the more sensitive wild-type counterparts, we compared the expression of chemokines versus the amount of infectious virus recovered from the anterior segment of the eye and nervous system. Consistent with our predicted outcome, the level of infectious virus recovered in the iris, trigeminal ganglia, and brainstem of resistant versus sensitive mice correlated with chemokine production; that is, the less virus recovered the less chemokine (CCL2, CCL3, CCL5, CXCL9, and CXCL10) produced. In contrast to the nervous system and iris, there was no correlation between chemokine expression and level of infectious virus recovered in the cornea. We interpret these results as suggesting chemokine expression within the cornea in response to herpes simplex virus type 1 infection is driven by factors other than antigenic stimulation.

Animals↗

PubMed1999

Efficiency of drug resistance genotypic tests in specimens with low HIV viral load.

The early recognition of resistance to antiretroviral agents could allow a rapid switch in therapy and therefore avoid the accumulation of mutations and reduce the risk of cross-resistance. However, the efficiency of genotypic tests in specimens with low viral load (VL) is severely compromised since human immunodeficiency virus (HIV) RNA in these samples often goes unrecognized. The frequency of results provided by a line probe assay (LiPA, Murex), a commercially available drug resistance test and a home-made point mutation assay (PMA) for recognizing the codon 151 multidrug-resistance mutation was examined in 664 plasma samples stratified with respect to VL values. Overall, 421 (63%) samples could be interpreted by both LiPA and PMA. The sensitivity decreased as plasma VL lowered: 89% for samples with VL > 10,000 HIV RNA copies/ml, 77% for those with VL between 500 and 10,000 HIV RNA copies/ml and 37% for specimens with VL < 500 HIV RNA copies/ml. A good agreement existed comparing the sensitivity of the home-made PMA and LiPA. Although the former tends to produce more results, the difference did not achieve statistical significance. Our results support that new, more sensitive, HIV RNA extraction methods need to be implemented for the rapid recognition of drug-resistant mutants in patients experiencing an early rebound in plasma viraemia.

Acquired Immunodeficiency Syndrome↗

PubMed1997

Course of specific T lymphocyte cytotoxicity, plasma and cellular viral loads, and neutralizing antibody titers in 17 recently seroconverted HIV type 1-infected patients.

Relationships were sought between specific anti-HIV cytotoxic T lymphocyte (CTL) responses (against structural and regulatory proteins of the HIV-1 LAI isolate) and plasma and cellular viral loads (VLs) in 17 recently HIV-1-infected patients including 3 displaying asymptomatic primary infection (PI) followed up for 12 months. Plasma VL was correlated directly with CD8 counts and inversely with CD4 counts. Cytotoxic reactions were observed in all patients and directed mainly against structural proteins. The earliest CTL responses were against Gag and Env proteins detected in 87 and 75% of the subjects, respectively, within the first month following PI. Anti-Env and Gag cytotoxic responses were inversely correlated with the plasma VL. Reactions against the pol gene products were thought to be either less involved in or less efficient for the initial decrease of viremia. Responses against regulatory gene products were weak and variable, apart from Nef, which was recognized by half of the subjects. Neutralizing antibodies were not detected before month 3, and were found only in six patients at subsequent times. Two of three patients with asymptomatic PI had a low viral burden and either a delayed response or one limited to a few protein CTL responses, suggesting that the magnitude of the CTL response depends on the initial plasma VL. The third patient displayed viral and CTL parameters identical to those of the patients with symptomatic PI. However, two subjects with symptomatic PI exhibited similarly low plasma VL and moderate CTL responses. Overall, the results suggest that the CTL response may not be the sole factor controlling viremia.

Acquired Immunodeficiency Syndrome↗

PubMed2007

Triple antiretroviral prophylaxis administered during pregnancy and after delivery significantly reduces breast milk viral load: a study within the Drug Resource Enhancement Against AIDS and Malnutrition Program.

BACKGROUND: The administration of antiretroviral therapy to lactating women could represent a possible strategy to reduce postnatal HIV transmission. In this study, we assessed the effect of antiretroviral treatment on breast milk viral load and determined plasma and breast milk drug concentrations in pregnant women receiving highly active antiretroviral therapy (HAART). METHODS: We studied 40 women receiving zidovudine, lamivudine, and nevirapine from 28 weeks of gestation to 1 month postpartum (group A) and 40 untreated pregnant women (group B). Blood and breast milk samples were collected at delivery and 7 days postpartum. RESULTS: Women in group A had received a median of 85 days of therapy before delivery. Median breast milk concentrations of nevirapine, lamivudine, and zidovudine were 0.6, 1.8, and 1.1 times, respectively, those in maternal plasma. HIV RNA levels in breast milk were significantly lower in group A than in group B (median of 2.3 vs. 3.4 log at delivery and 1.9 vs. 3.6 log at day 7; P < 0.001 for both comparisons). CONCLUSIONS: Antiretroviral drugs administered during the last trimester of pregnancy and after delivery reach levels similar to or higher than plasma concentrations in breast milk and can significantly reduce HIV RNA levels. Our data support the potential role of maternal HAART prophylaxis in reducing the risk of breast-feeding-associated transmission.

Adolescent↗

PubMed2002

Improvement of AMPLICOR human immunodeficiency virus type 1 viral load test (version 1.5) by addition of a coprecipitant during the RNA isolation step.

The effect of the addition of a coprecipitant during the RNA isolation step on the analytical performance of the COBAS AMPLICOR human immunodeficiency virus type 1 (HIV-1) Monitor (version 1.5; Roche) viral load test was tested. Thirty-six specimens including patient samples, positive control samples, and negative control samples were processed in the presence and absence of the Pellet Paint coprecipitant. Specimens processed without the coprecipitant had lower RNA yields, as evidenced by a lower signal for the quantitation standard (QS). In addition, the results for all samples processed with the coprecipitant were acceptable on the basis of the optical density (OD) reading for the QS, whereas the result for one specimen processed without the coprecipitant was unacceptable on the basis of the OD reading for the QS, which required the assay to be repeated. Furthermore, the use of the coprecipitant improved the overall precision of the assay.

Chemical Precipitation↗

PubMed2005

Viral load responses to HAART is an independent predictor of a new AIDS event in late stage HIV infected patients: prospective cohort study.

BACKGROUND: A sizeable number of HIV-infected patients receiving HAART do not maintain prolonged virologic suppression. We evaluated long-term HIV viral load (VL) responses to HAART as a risk factor for AIDS events (AE) that is independent of CD4 responses. METHODS: A cohort of patients with pre-therapy CD4 < 200/mm3 who had CD4 and VL measurements for > one year after receiving HAART at a university clinic were prospectively enrolled. Cox proportional multivariate regression model was used to determine whether CD4 and VL responses were independently associated with new AE. RESULTS: The patient (N = 214) mean baseline CD4 = 92/mm3, VL = 219,000 c/mL and follow-up duration 42.3 months (range 13-72 months). A new AE occurred in 56 patients; CD4 cell count response to HAART that remained < 200/mm3 throughout the study period was a significant risk factor for new AE (RR = 9.7-12.5; p < 0.001). Similarly, VL responses that remained > 5,000 c/mL during this period was also a significant risk factor (RR = 6.7-12.8; p = 0.001) that was independent of CD4 response adjusted for <> 200/mm3. CONCLUSION: Maintaining adequate long-term virologic responses to HAART provides a clinical benefit independent of CD4 responses.

Journal Article↗

PubMed1994

Quantitation of human immunodeficiency virus type 1 during pregnancy: relationship of viral titer to mother-to-child transmission and stability of viral load.

To develop strategies to prevent mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1), it is important to define the factors determining it. We examined the relationship between maternal HIV-1 titer and the occurrence of mother-to-child transmission. In addition, we quantitated HIV-1 longitudinally in mothers during pregnancy, at delivery, and up to 1 year postpartum. To examine transmission, we prospectively studied 19 mother-child pairs; in 5 pairs, HIV-1 transmission occurred. We used endpoint dilution culture of peripheral blood mononuclear cells to determine maternal viral titer and found that although 4 of 6 (67%) women with viral titers of > or = 125 HIV-1 infectious units per 10(6) cells transmitted HIV-1 to their infants, only 1 of 13 (7.6%) women with lower viral titers transmitted (P = 0.01). Twelve of the 19 mothers had HIV-1 loads determined serially 3-8 times over periods ranging from 18 to 65 weeks. Viral titers varied greatly between the 12 women, but the viral load in each woman remained stable over time. In this cohort, HIV-1 viral load remained stable during pregnancy and the greater the maternal viral burden, the more likely that transmission occurred. These two related findings suggest that determination of HIV-1 titers early in pregnancy may predict which women are at high risk of transmitting to their infants and may be used to counsel HIV-1-infected women of childbearing age. These data identify maternal viral titer as a major determinant of mother-to-child HIV-1 transmission and thereby provide the scientific rationale for therapeutic strategies designed to interrupt transmission by lowering viral load.

Acquired Immunodeficiency Syndrome↗

PubMed1997

HIV viral load and CD4+ lymphocyte counts in subjects coinfected with HTLV-I and HIV-1.

Reports indicate that there is a dissociation between markers of HIV disease progression and clinical stage among subjects coinfected with human T-cell lymphotropic virus type I (HTLV-I) and HIV. HTLV-I coinfection does not appear to affect HIV viral load, currently considered to be the best marker of HIV disease progression. We measured HIV RNA levels in stored serum samples from 23 subjects with coinfection and 92 subjects with HIV single infection and examined the correlation with the CD4+ lymphocyte count. Subjects were recruited from an ongoing HIV cohort study in Rio de Janeiro, Brazil. In both groups, CD4+ lymphocyte counts declined with increasing levels of HIV RNA. In a linear regression analysis adjusting for HIV RNA serum level, coinfected individuals had an estimated 78% higher CD4+ lymphocyte count than those with single infection. Simultaneous adjustment for beta2-microglobulin level increased the difference, with coinfected individuals having 146% (p = 0.005, 95% CI: 32% to 359%) higher CD4+ counts. These data suggest that the higher CD4+ lymphocyte counts associated with coinfection do not provide immunologic benefit and may reflect HTLV-I-associated nonspecific lymphocyte proliferation. The results of this and other studies suggest that the CD4+ count cutoff values used in making clinical decisions in HIV infection may not be appropriate in coinfection. As with HIV single infection, HIV virus load may be the optimal surrogate marker for subjects with coinfection.

Acquired Immunodeficiency Syndrome↗

PubMed1998

Comparison of an amplified enzyme-linked immunosorbent assay with procedures based on molecular biology for assessing human immunodeficiency virus type 1 viral load.

The sensitivity of the enzyme-linked amplified sorbent test (ELAST) was compared with those of other classic enzyme-linked immunosorbent assays (ELISAs), with or without previous acidic immunocomplex dissociation (ICD), in a series of samples at different stages of human immunodeficiency virus type 1 (HIV-1) infection. The limit of viral detection of ELAST was assessed with fresh HIV-1 preparations quantified by reverse transcription-PCR and with the P24 antigen (Ag) Sanofi Pasteur Calibrator containing lyophilized virus. The P24 Ag detection capacity of ELAST was compared with that of NASBA in samples obtained from infected subjects with less than 250 CD4+ cells. The results of the present study show that ELAST was the most sensitive method for detecting P24 Ag compared to classic ELISA and ICD plus ELISA. ELAST was able to detect 0.5 pg of P24 Ag per ml in a whole virus preparation and the equivalent of 330 to 1,000 RNA copies/ml of HIV. The rate of detection of P24 Ag was always higher in subjects with low levels of anti-P24 antibodies. The number of positive results was dramatically enhanced (from 37% to 94% for subjects with <250 CD4+ cells) when the incubation period was prolonged from 1 to 16 h. In a third series of 84 samples (<250 CD4+ cells) tested in parallel, NASBA yielded 83% of the positive results and ELAST yielded 79%. Considering the high sensitivity, low cost, simplicity of equipment (only a plate reader), and possibility for full automation, ELAST appears to be a promising new tool for measuring viral load, especially in areas with few resources, in which the procedures based on molecular biology techniques may be difficult to install.

CD4 Lymphocyte Count↗