saquinavir and Viremia

The authors had for aim to describe the effectiveness and the safety of a saquinavir/ritonavir (SQV/r) regimen, 1000/100mg twice daily, in HIV-infected pregnant patients.. We made a prospective and observational study of HIV positive female patients beginning or going on SQV/r antiretroviral treatment (ART) during pregnancy.. Sixty-two patients were enrolled from July 2007 to June 2009 in 10 infectious diseases units in France. Thirty-six women (group 1) were ART naive on inclusion, 20 (group 2) had been previously treated and then switched to SQV/r, six (group 3) were treated with SQV/r before pregnancy. 58 patients delivered while on SQV/r regimen after a median pregnancy duration of 39 WA. Eighty percent had a viral load below 50 copies/mL and 93% below 400 copies/mL: respectively 77% and 93.5% in group 1, 83% and 89% in group 2, 83% and 100% in group 3. The median SQV minimum concentrations (C(min)) measured at the third trimester and at delivery were adequate, respectively 0.91 mg/L and 0.86 mg/L. Most women (52%) had a vaginal delivery; 12 (21%) had an elective caesarean section, for obstetrics factors in eight cases. None of the newborns were HIV-infected at 6 months of age (n = 59, one death at day 3). Only one severe adverse event occurred due to saquinavir (maternal grade 3 hepatotoxicity).. SQV/r 1000/100mg twice daily seems to be effective and safe in HIV-infected pregnant women with adequate saquinavir C(min).

Topics: Adult; CD4 Lymphocyte Count; Chemical and Drug Induced Liver Injury; Cohort Studies; Delivery, Obstetric; Drug Therapy, Combination; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; HIV-2; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Male; Pregnancy; Pregnancy Complications, Infectious; Pregnancy Outcome; Prospective Studies; Ritonavir; Saquinavir; Treatment Outcome; Viral Load; Viremia; Young Adult; Zidovudine

The treatment of HIV infection during pregnancy significantly and substantially reduces the risk of mother-to-child transmission. Although triple therapy is the standard of care for management of HIV infection in adults, the safety of many approved antiretroviral agents in pregnancy is not currently established.. An open-label pilot study conducted in Thailand and the UK of the safety of saquinavir soft-gel capsules 1200 mg three times daily administered in the second and third trimester of pregnancy in combination with local standard-of-care antiretroviral therapy. Infants received local standard-of-care antiretroviral therapy after delivery. Steady-state pharmacokinetics were performed in a subset of mothers at 4 weeks after the commencement of saquinavir therapy and paired samples collected from the mother and infant cord blood at delivery.. Eighteen antiretroviral-naive pregnant women with a mean viral load of 4.2 log10 and CD4 cell count of 481/mm(3) were recruited. All patients received zidovudine and 3 (all in the UK) received lamivudine. There were no serious adverse events and no discontinuations due to adverse events. Viral load declined by 1.6 log10 at week 4 and was less than 400 copies/mL at delivery in 16/17 mothers. Sixteen live births were recorded, with two in utero deaths-one secondary to an accident and the second due to antiphospholipid syndrome. Both deaths were considered by investigators to be unrelated to study therapy. All infants were HIV negative at subsequent follow-up and no fetal abnormalities were observed. Pharmacokinetic data suggested that mothers had relatively low exposures to saquinavir despite an excellent virologic response. Saquinavir was not detected in cord blood.. Saquinavir soft-gel capsules are well tolerated during pregnancy and are not associated in this small study with birth abnormalities. Transmission of HIV infection from mother to child was successfully prevented in all cases. Low maternal exposures of saquinavir were noted. However, these did not appear to affect virologic efficacy of the combination. Samples from cord blood indicate minimal fetal exposure to saquinavir.

Topics: Adult; Anti-HIV Agents; Female; HIV Infections; Humans; Infant, Newborn; Infectious Disease Transmission, Vertical; Lamivudine; Pregnancy; Pregnancy Complications, Infectious; Safety; Saquinavir; Thailand; United Kingdom; Viremia; Zidovudine

To assess the effects of five-drug combination therapy on HIV-1 load in lymph nodes and subsequent maintenance with four and three drugs.. Ten pharmacotherapeutically naive patients received a combination of zidovudine, lamivudine, didanosine, ritonavir, and saquinavir for 24 weeks, then zidovudine, lamivudine, didanosine, and saquinavir for the next 24 weeks, and finally zidovudine, lamivudine, and saquinavir for the last 24 weeks. HIV-1 RNA in lymph nodes was measured using quantitative polymerase chain reaction (PCR) at baseline, after 12, 24, 48, and 78 weeks. Plasma HIV-1 RNA, proviral DNA in peripheral blood mononuclear cells (PBMCs), circulating lymphocyte subsets, and protease inhibitor levels in blood were also regularly measured. Genotypic resistance was assessed in the different compartments in 2 patients who were failed by therapy.. HIV-1 RNA decreased in lymph nodes in 9 patients and was stable in 1 despite initial control of plasma replication <20 copies/ml in each patient. Lymph node levels rebounded in 1 patient at week 72 as a result of lack of adherence and remained stable in the 8 others despite maintenance regimens. This represents a mean drop of -3.17 log in lymph nodes for the 8 patients maintaining undetectable viremia at 72 weeks. In the patient with stable lymph node viral RNA, selection of the M184V mutation was demonstrated at this level before detection in plasma and low blood saquinavir levels were found throughout the study. Continuous improvements in immune parameters were observed in all cases, although PBMC proviral DNA levels either showed a continuous decrease or stabilized to a plateau.. More complex regimens do not perform better in lymph nodes than classic triple therapy. The persistence of HIV-1 RNA in lymph nodes could be related with cellular resistance mechanisms rather than an insufficient potency of the regimens.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Biopsy; CD4 Lymphocyte Count; Didanosine; DNA, Viral; Drug Therapy, Combination; Female; France; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Lamivudine; Lymph Nodes; Lymphocyte Subsets; Lymphocytes; Male; Polymerase Chain Reaction; Ritonavir; RNA, Viral; Saquinavir; Time Factors; Viral Load; Viremia; Virus Replication

Therapeutic options are limited for patients refractory to triple therapy with two reverse transcriptase inhibitors and one protease inhibitor. Preliminary results showing favorable effects of protease inhibitor combination therapy with nelfinavir and saquinavir due to inhibition of metabolism by cytochrome P450 (CYP450) prompted us to study this combination. - Thirteen patients with incomplete suppression of plasma HIV-RNA were enrolled and treatment was started with nelfinavir 750 mg tid and saquinavir 400 mg bid. Saquinavir-dosage was escalated in weekly intervals to 400 mg tid and 600 mg tid, respectively. All doses were given with food, and plasma levels of saquinavir and nelfinavir were assessed 4 hours post-dosing after 1, 2, 3, 4 and 8 weeks. Treatment was considered virologically efficacious if HIV-viral load was reduced by at least 0.5 log10 from baseline. - Double protease inhibitor-treatment with nelfinavir and saquinavir was virologically efficacious in 5/13 (39%) patients after 4 weeks but only in 4/13 (31%) patients after 8 and 1/13 (8%) after 16 and 24 weeks, respectively. No statistical difference in plasma concentrations was observed when saquinavir was administered in increasing doses of 400 mg bid, 400 mg tid or 600 mg tid in combination with nelfinavir. 5/13 (39%) patients developed diarrhea (>4/d), no other serious side-effects were observed. By eight weeks, the mean CD4 count for all patients was significantly higher when compared to baseline. - In patients refractory to standard triple therapy the combination of nelfinavir and saquinavir showed significant elevation of CD4-count, but only short term virological efficacy in a minority of patients. Plasma concentrations of saquinavir could not be increased by weekly dose escalation of the drug from 400 mg bid to 600 mg tid. Saquinavir drug concentrations of 600 mg saquinavir tid and nelfinavir showed rather non-significant lower values when compared to historical controls treated with a double-dose 1200 mg saquinavir tid regimen alone. We conclude that in these patients the combination of nelfinavir plus saquinavir has no advantage in terms of increasing bioavailibility of saquinavir or virological efficacy. During short observation time a beneficial effect on CD4-count was observed.

Topics: Adult; Anti-HIV Agents; Biological Availability; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Dose-Response Relationship, Drug; Drug Resistance, Microbial; Drug Therapy, Combination; Enzyme Inhibitors; Female; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Male; Middle Aged; Mixed Function Oxygenases; Nelfinavir; Prospective Studies; Reverse Transcriptase Inhibitors; RNA, Viral; Salvage Therapy; Saquinavir; Treatment Outcome; Viral Load; Viremia

Combination antiretroviral therapy with ritonavir and saquinavir has established potent and durable activity on plasma viremia. CNS HIV infection may be sequestered from drug therapy that does not penetrate the blood-brain barrier. Penetration of these protease inhibitors into the cerebrospinal fluid (CSF) and CSF HIV RNA levels on such therapy has not been well described.. In a cross-sectional study, 28 HIV1-infected study subjects were evaluated either before initiation of or before maximal response to ritonavir-saquinavir therapy, during maximal plasma virologic response, and after virologic failure. Simultaneous samples of plasma and cerebrospinal fluid were obtained from 24 study subjects to measure HIV RNA and protease inhibitor levels.. Across the treatment groups, a strong correlation was found between plasma and CSF HIV RNA levels (r = 0.870; p < .001). In each study subject with plasma HIV RNA levels below assay limit (80 copies/ml), the CSF HIV RNA level was also below the limit of quantitation. Low levels of saquinavir (<2 ng/ml) and ritonavir (<25 ng/ml) in the CSF were observed, with a CSF:plasma drug concentration ratio of < or = 0.005 (0.5%) in all study subjects evaluated (n = 11). The plasma:CSF HIV RNA ratio was high before or early in treatment (median, 38; interquartile range [IQR], 13,97), but low (median, 0.29; IQR, 0.17, 7.5) in those failing therapy (group C, p < .001).. CSF ritonavir and saquinavir levels are consistent with the estimated known fraction of unbound drug in plasma (<2%). Across these treatment response groups, suppression of plasma viremia can predict low CSF HIV RNA levels. This correlation may represent HIV RNA transport and equilibrium between CSF and plasma, or it may represent CNS anti-HIV activity of protease inhibitors. The low drug levels and inverted ratio of HIV RNA in the CSF compared with plasma early in plasma virologic breakthrough suggests CSF virologic failure may contribute to failure of plasma virologic response.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; CD4 Lymphocyte Count; Cross-Sectional Studies; Drug Therapy, Combination; HIV Infections; HIV-1; Humans; Patient Selection; Ritonavir; RNA, Viral; Saquinavir; Treatment Failure; Treatment Outcome; Viral Load; Viremia

The impact of human immunodeficiency virus (HIV) protease inhibitors on hepatitis C (HCV) viremia was assessed in 19 patients infected with both HIV and HCV. HIV and HCV RNA levels were measured before and during treatment with protease inhibitors. Before treatment, mean levels of HCV RNA were 5.3 log for HCV RNA and 5.0 log for HIV RNA. CD4 lymphocyte counts were 63/mm3. After 6 weeks of treatment, a mean reduction of 2.1 log10 in HIV RNA (P < .001) and a mean (+/-SE) increase of 73 (+/-21) CD4 and 296 (+/-70) CD8 cells were observed (P < .05). In contrast, both HCV viremia (+0.4 log +/- 0.1) and alanine aminotransferase increased (P < .04). HCV RNA levels returned to baseline after 17 and 32 weeks of treatment. Thus, potent anti-HIV regimens with protease inhibitors may temporarily worsen HCV status despite improvement of HIV parameters.

Topics: Anti-HIV Agents; Drug Therapy, Combination; Female; Hepatitis C; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Male; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Viremia

Fine-needle aspiration was used to collect lymph node cells (LNC) from 9 antiretroviral-naive patients entering a double-blind single- or combined-drug study of zidovudine, zalcitabine, and saquinavir. LNC were obtained twice before and 1 and 6 months after initiation of treatment. The effect of antiretroviral treatment on virus load ranged from no response to a dramatic decrease in plasma and LNC human immunodeficiency virus (HIV) RNA levels. The decrease in unspliced or spliced (or both) HIV RNAs in LNC was correlated with but consistently smaller than the decrease in plasma viremia. When present, the increase in blood CD4 T cells was, in general, moderate and transient. However, a striking rise in blood CD4 T cell count and in LNC CD4:CD8 ratio was observed in the 1 patient with the deepest sustained decrease in HIV RNA level in both plasma and lymph nodes.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; Biopsy, Needle; CD4 Lymphocyte Count; CD4-CD8 Ratio; Double-Blind Method; Drug Monitoring; Drug Therapy, Combination; HIV-1; Humans; Lymph Nodes; Polymerase Chain Reaction; Regression Analysis; RNA Splicing; RNA, Viral; Saquinavir; Single-Blind Method; Viremia; Zalcitabine; Zidovudine

To assess the safety, efficacy and plasma drug levels of the combination of ritonavir plus saquinavir for the treatment of advanced HIV infection.. Multicentre pilot study.. Eighteen protease inhibitor-naive patients, with intolerance or contraindication to reverse transcriptase inhibitors, a median CD4 cell count of 12 x 10(6)/l (range, 1-50 x 10(6)/l), and a median HIV viraemia of 5.25 log10 copies/ml (range, 4.00-6.13 log10 copies/ml).. Patients received 600 mg twice daily of both ritonavir and saquinavir. Viraemia was measured at baseline and at weeks 5, 9 and 13. Response was defined as a drop of viraemia of more than 1 log10 at week 5. Plasma drug levels were determined after at least 3 weeks of combined treatment: samples were collected before and 1, 2, and 4 h after the morning ingestion of both drugs. The protease gene was sequenced at baseline and under treatment.. Among the 16 patients evaluable at week 5, 11 were responders, and among these patients, six remained responders at week 13 (two with undetectable viraemia). Study discontinuations were due to side-effects (n = 4), patient choice (n = 3), protocol violation (n = 1) and death (n = 1). Responders had higher drug levels than non-responders (P < 0.01 for saquinavir, P = 0.04 for ritonavir). In two non-responders, development of multiple new mutations at positions 10, 20, 48, 82, 84 and 90 was observed after 5-13 weeks.. The response to ritonavir plus saquinavir in advanced HIV infection is unpredictable. A minority of patients respond with disappearance of HIV viraemia. In other patients, rapid cumulative emergence of protease mutations conferring resistance to treatment cannot always be prevented by good compliance and relatively high plasma drug levels.

Topics: Acquired Immunodeficiency Syndrome; Anti-HIV Agents; CD4 Lymphocyte Count; CD4-CD8 Ratio; Cohort Studies; Drug Resistance, Microbial; Drug Therapy, Combination; Female; HIV Protease; HIV Protease Inhibitors; Humans; Male; Mutation; Pilot Projects; Ritonavir; Saquinavir; Viremia

To evaluate the efficacy and safety of high-dose therapy with the human immunodeficiency virus (HIV) protease inhibitor saquinavir and to establish the duration of the effect of this therapy.. Open-label study.. Clinical research referral center.. 40 adults with human immunodeficiency virus type 1 (HIV-1) infection and CD4+ T-cell counts of 200 to 500 cells/mm3.. Monotherapy with 3600 mg or 7200 mg of saquinavir per day, in six divided doses, for 24 weeks.. Patients were monitored for adverse events and were evaluated monthly for CD4+ T-cell count, HIV-1 viral load (as measured by reverse transcriptase polymerase chain reaction [PCR] for plasma HIV RNA levels), immune-complex-disassociated p24 antigen levels, peripheral blood mononuclear cell viral DNA levels (as measured by PCR), and resistance mutations to saquinavir. Quantitative peripheral blood mononuclear cell cultures were also done every 2 months.. The low-dose saquinavir regimen (3600 mg/d) resulted in a maximal mean decrease in plasma HIV RNA levels of 1.06 log RNA copies/mL of plasma and a mean maximal increase in CD4 counts of 72 cells/mm3. At week 24, the plasma HIV RNA level remained 0.48 log RNA copies/mL of plasma lower than baseline (P < 0.001) and the CD4 count remained 31 cells/mm3 higher than baseline (P = 0.165). The high-dose saquinavir regimen (7200 mg/d) produced a mean maximal decrease in the plasma HIV RNA level of 1.34 log RNA copies/mL of plasma and a mean maximal increase in CD4 count of 121 cells/mm3. At week 24, the plasma HIV RNA level remained 0.85 log RNA copies/mL of plasma lower than baseline (P < 0.001) and the CD4 count remained 82 cells/mm3 higher than baseline (P = 0.002). The high-dose regimen produced a greater reduction in plasma HIV RNA level (P = 0.08), a greater reduction in peripheral blood mononuclear cell cultures (P = 0.008), and a greater increase in CD4 count (P = 0.002) than did the low-dose regimen. Higher plasma drug concentrations in individual patients correlated with greater reductions in plasma HIV RNA levels over the two doses. Nine patients receiving the low-dose regimen and four patients receiving the high-dose regimen developed key saquinavir resistance mutations. Adverse reactions, most commonly gastrointestinal problems and elevated serum aminotransferase levels, were more common in patients receiving the high-dose regimen, but most adverse events were mild and all were reversible.. Saquinavir is a potent antiviral agent that has a favorable toxicity profile at high doses. Higher doses produce a greater and more durable suppression of viral load and elevation in CD4+ T-cell counts and may delay the development of resistance mutations. Therapy with high-dose saquinavir alone or in combination with other antiretroviral agents should be investigated further.

Topics: Adult; Base Sequence; CD4 Lymphocyte Count; DNA Primers; Dose-Response Relationship, Drug; Female; HIV Core Protein p24; HIV Infections; HIV Protease; HIV Protease Inhibitors; HIV-1; Humans; Isoquinolines; Male; Middle Aged; Molecular Sequence Data; Mutation; Quinolines; RNA, Viral; Saquinavir; Viremia

OBJECTIVE To determine the rate of virological rebound and factors associated with rebound among patients on highly active antiretroviral therapy (HAART) with previously undetectable levels of viraemia. DESIGN An observational cohort study of 2444 patients from the EuroSIDA study. METHODS Patients were followed from their first viral load under 400 copies/ml to the first of two consecutive viral loads above 400 copies/ml. Incidence rates were calculated using person-years of follow-up (PYFU), Cox proportional hazards models were used to determine factors related to rebound. RESULTS Of 2444 patients, 1031 experienced virological rebound (42.2%). The incidence of rebound decreased over time; from 33.5 in the first 6 months after initial suppression to 8.6 per 100 PYFU at 2 years after initial suppression (P < 0.0001). The rate of rebound was lower for treatment-naive compared with treatment-experienced patients. In multivariate models, patients who changed treatment were more likely to rebound, as were patients with higher viral loads on starting HAART. Treatment-naive patients were less likely to rebound. Among pretreated patients, those who were started on new nucleosides were less likely to rebound. CONCLUSION The rate of virological rebound decreased over time, suggesting that the greatest risk of treatment failure is in the months after initial suppression. Treatment-naive patients were at a lower risk of rebound, but among drug-experienced patients, those who added new nucleosides had a lower risk of rebound, as were patients with a good immunological response.

Topics: Adult; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Drug Administration Schedule; Europe; Female; Follow-Up Studies; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Male; Middle Aged; Proportional Hazards Models; Prospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Treatment Failure; Viral Load; Viremia

Sustained elevations in CD4 cell counts commonly occur despite incomplete viral suppression with protease inhibitor-based antiretroviral therapy.. To determine the incidence and risk factors associated with return of CD4 cell count to pre-therapy levels in patients experiencing virologic failure of protease inhibitor therapy.. This is a clinic-based cohort study of HIV-infected adults who failed to maintain durable viral suppression on a protease inhibitor-based regimen.. Virologic failure was defined as persistent plasma HIV RNA level > 500 copies/ml. Immunologic failure was defined as return of CD4 cell count to pre-therapy levels.. A total of 291 patients experienced virologic failure on a protease inhibitor-based regimen and had a treatment-mediated CD4 cell increase above pre-therapy levels at the time of virologic failure. If patient data were censored at the time a successful salvage regimen was initiated, then the median time to immunologic failure after the onset of virologic failure was 3 years. If patient data were also censored at the time therapy was discontinued, then 36.8% of the cohort experienced immunologic failure after 3 years of continuous virologic failure. The change in viral load from a pre-treatment baseline, and not the absolute level of viremia achieved, was a strong and independent predictor of immunologic failure. Discontinuing therapy was associated with immunologic failure independent of viral load changes.. Reduction in T CD4+ cell numbers may eventually occur during prolonged virologic failure of a protease inhibitor-based regimen and is predicted by the degree of virologic suppression below a pre-therapy 'set-point'.

Topics: Adult; Antiretroviral Therapy, Highly Active; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Disease Progression; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Indinavir; Nelfinavir; Ritonavir; RNA, Viral; Saquinavir; Time Factors; Treatment Failure; Viremia

Major T-cell receptor beta chain variable region (TCRBV) repertoire perturbations are temporally associated with the down-regulation of viremia during primary human immunodeficiency virus (HIV) infection and with oligoclonal expansion and clonal exhaustion of HIV-specific cytotoxic T lymphocytes (CTLs). To determine whether initiation of antiretroviral therapy (ART) or highly active antiretroviral therapy (HAART) during primary infection influences the dynamics of T-cell-mediated immune responses, the TCRBV repertoire was analyzed by semiquantitative polymerase chain reaction in serial blood samples obtained from 11 untreated and 11 ART-treated patients. Repertoire variations were evaluated longitudinally. Stabilization of the TCRBV repertoire was more consistently observed in treated as compared with untreated patients. Furthermore, the extent and the rapidity of stabilization were significantly different in treated versus untreated patients. TCRBV repertoire stabilization was positively correlated with the slope of HIV viremia in the treated group, suggesting an association between repertoire stabilization and virologic response to treatment. To test whether stabilization was associated with variations in the clonal complexity of T-cell populations, T-cell receptor (TCR) heteroduplex mobility shift assays (HMAs) were performed on sequential samples from 4 HAART-treated subjects. Densitometric analysis of HMA profiles showed a reduction in the number of TCR clonotypes in most TCRBV families and a significant decrease in the total number of clonotypes following 7 months of HAART. Furthermore, a biphasic decline in HIV-specific but not heterologous CTL clones was observed. This indicates that ART leads to a global reduction of CD8(+) T-cell oligoclonality and significantly modulates the mobilization of HIV-specific CTL during primary infection. (Blood. 2000;95:1743-1751)

Topics: Acute Disease; Anti-HIV Agents; Clone Cells; Didanosine; Drug Administration Schedule; Drug Therapy, Combination; Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Indinavir; Lamivudine; Lymphocyte Activation; Polymerase Chain Reaction; RNA-Directed DNA Polymerase; Saquinavir; T-Lymphocytes, Cytotoxic; Viremia; Zidovudine

Effective therapeutic interventions and clinical care of adults infected with HIV-1 require an understanding of factors that influence time of response to antiretroviral therapy. We have studied a cohort of 118 HIV-1-infected subjects naive to antiretroviral therapy and have correlated the time of response to treatment with a series of virological and immunological measures, including levels of viral load in blood and lymph node, percent of CD4 T cells in lymph nodes, and CD4 T-cell count in blood at study entry. Suppression of viremia below the limit of detection, 50 HIV-1 RNA copies/mL of plasma, served as a benchmark for a successful virological response. We employed these correlations to predict the length of treatment required to attain a virological response in each patient. Baseline plasma viremia emerged as the factor most tightly correlated with the duration of treatment required, allowing us to estimate the required time as a function of this one measure.

Topics: Adult; Anti-HIV Agents; Carbamates; CD4 Lymphocyte Count; CD4-Positive T-Lymphocytes; Cohort Studies; Dideoxynucleosides; Furans; HIV Infections; HIV Protease Inhibitors; HIV Reverse Transcriptase; HIV-1; Humans; Lamivudine; Lymph Nodes; Nelfinavir; Reverse Transcriptase Inhibitors; RNA, Viral; Saquinavir; Stavudine; Sulfonamides; Time Factors; Viral Load; Viremia; Zidovudine

Modified, human immunodeficiency virus (HIV)-inoculated thy/liv-SCID-hu mice were used to evaluate the in vivo efficacy of antiretroviral drugs. Ritonavir treatment alone initially suppressed plasma viremia, but the viremia recurred with the appearance of ritonavir-resistant HIV isolates. Multidrug therapy suppressed plasma HIV RNA to undetectable levels; however, plasma viremia returned after therapy was stopped, showing that the therapy did not completely suppress HIV infection in the thymic implant. When thy/liv-SCID-hu mice were treated with a combination of zidovudine, lamivudine, and ritonavir immediately after inoculation with HIV, cocultures of the thymic implants remained negative for HIV even 1 month after therapy was discontinued, suggesting that acute treatment can prevent the establishment of HIV infection. Thus, these modified thy/liv-SCID-hu mice should prove to be a useful system for evaluating the effectiveness of different antiretroviral therapies on acute and chronic HIV infection.

Topics: Animals; Anti-HIV Agents; Chronic Disease; Drug Resistance, Microbial; Drug Therapy, Combination; Fetal Tissue Transplantation; Flow Cytometry; HIV Infections; HIV-1; Lamivudine; Leukocytes, Mononuclear; Liver Transplantation; Mice; Mice, SCID; Recurrence; Ritonavir; RNA, Viral; Saquinavir; Thymus Gland; Viremia; Zidovudine

To evaluate the clinical and biological impact of protease inhibitors on HIV-associated Kaposi's sarcoma.. A cohort of 10 patients included prospectively from April 1996 to June 1997 were studied in one institutional centre after initiation of protease inhibitors.. All patients but one (stable disease) had progressive Kaposi's sarcoma. Three out of 10 patients had stopped specific chemotherapy for Kaposi's sarcoma for more than 4 weeks, three were still under chemotherapy, and four had never received specific treatment of Kaposi's sarcoma. Plasma HIV viral load, human herpesvirus (HHV)-8 viraemia in peripheral blood mononuclear cells (PBMC), and CD4 cell count were sequentially assessed from the beginning of therapy. For six patients, a semiquantitative evaluation of HHV-8 viral load in the Kaposi's sarcoma lesions was performed during treatment using polymerase chain reaction.. After initiation of HIV triple therapy with protease inhibitors, we observed six complete responses, two partial responses, and two patients with progressive disease. All patients had undetectable plasma HIV viral load within 2 months of treatment. Undetectable HHV-8 viraemia in PBMC occurred in seven out of eight patients with partial or complete response and in none of the progressive patients. A decrease or negation of HHV-8 viral load in Kaposi's sarcoma lesions was observed in two complete responders.. Our results suggest that antiviral therapy with protease inhibitors are clinically efficient in HIV-associated Kaposi's sarcoma and that there exists a correlation between clinical response and negation of HHV-8 viraemia.

Topics: Adult; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Didanosine; Dideoxynucleosides; Drug Therapy, Combination; Female; Herpesvirus 8, Human; HIV Protease Inhibitors; Humans; Indinavir; Lamivudine; Male; Middle Aged; Prospective Studies; Reverse Transcriptase Inhibitors; Ritonavir; Saquinavir; Sarcoma, Kaposi; Stavudine; Treatment Outcome; Viral Load; Viremia; Zalcitabine; Zidovudine

To study decay rates of productively and latently infected cells in peripheral blood and lymph nodes during triple antiretroviral therapy and the possible impact of interleukin-2 (IL-2) on viral kinetics.. In this non-randomized study, nine antiretroviral-naive HIV-positive patients received either saquinavir hard gel capsules 2400 mg three times daily (group I; four patients) or saquinavir soft gel capsules 1200 mg three times daily and IL-2 (group II), in both cases together with two nucleoside analogues. Plasma viraemia and lymphocyte subsets were analysed. Axillary lymph nodes were excised before and after 12 weeks of therapy. Lymph node sections were examined by in situ hybridization for HIV RNA, and productively infected cells were counted. Infection rates of FACS-sorted CD3, CD4 lymph node and peripheral blood mononuclear cells were determined by nested DNA PCR.. Baseline plasma HIV RNA levels ranged from < 25 to > 1 x 10(6) copies/ml and remained undetectable throughout the study in one patient in group I. Plasma viraemia became undetectable after 3 months in four patients (three in group I). Productively infected cells were markedly reduced in the follow-up lymph node specimens. HIV DNA-positive CD4 T cells were reduced in lymphoid tissue and peripheral blood in all six evaluable patients. There were no significant differences between the groups in the clearance rates of plasma virus and of HIV DNA-positive cells.. Combined antiretroviral therapy rapidly suppressed active HIV replication in plasma and lymphoid tissue. Latently infected cells were cleared at a slower rate. Viral clearance did not appear to be markedly affected by additional IL-2 therapy.

Topics: Adult; Anti-HIV Agents; Drug Therapy, Combination; Female; HIV Infections; Humans; Interleukin-2; Kinetics; Lymphoid Tissue; Male; Middle Aged; RNA, Viral; Saquinavir; Viremia; Zalcitabine; Zidovudine

To assess the antiretroviral effect of a combination of zidovudine, didanosine, lamivudine and saquinavir in plasma, peripheral blood mononuclear cells (PBMC) and lymph-node mononuclear cells (LNMC) after 8 weeks.. Ten HIV-1 antiretroviral therapy-naive patients were given a combination of oral zidovudine (200 mg three times daily), oral didanosine (200 twice a day), oral lamivudine (150 mg twice a day) and oral saquinavir (600 mg three times daily). HIV-1 plasma RNA was measured by quantitative reverse transcriptase (RT)-polymerase chain reaction (PCR). Infectious HIV-1 in PBMC and LNMC was measured by a coculture technique. HIV-1 RNA in PBMC and LNMC was quantified by RT-PCR. Proviral DNA titres in PBMC and LNMC were measured by endpoint dilution PCR. CD4 T-cells were analysed by flow cytometry.. CD4 cell counts rose in all patients (mean increase of 125 +/- 71 CD4 cells x 10(6)/l) and the benefit was greater for patients with fewer than 350 CD4 cells x 10(6)/l (mean increase of 159 +/- 74 CD4 cells x 10(6)/l). Plasma HIV-1 RNA decreased exponentially in all patients (mean decrease of 3.1 log10 after 8 weeks with a mean half-life of 2.2 +/- 0.6 days). HIV-1 RNA showed a decrease of 3.07 log10 in PBMC and of 2.1 log10 in LNMC. The decrease in plasma HIV-1 RNA was consistently associated with the decrease in LNMC. These data were supported by a concomitant drop of HIV-1 infectious titres in PBMC (mean decrease of 1.41 log10) and in LNMC (mean decrease of 2.54 log).. These data show a significant antiretroviral effect of this four-drug combination in blood and lymphoid tissues. However, a greater decrease in HIV-1 RNA was observed in PBMC and in plasma than in lymph node cells.

Topics: Adult; Anti-HIV Agents; CD4 Lymphocyte Count; Didanosine; DNA, Viral; Drug Therapy, Combination; Female; HIV Infections; HIV-1; Humans; Lamivudine; Leukocytes, Mononuclear; Lymph Nodes; Male; Polymerase Chain Reaction; RNA, Viral; Saquinavir; Viral Load; Viremia; Zidovudine

An overview of the Fourth International Workshop on HIV Drug Resistance held in 1995 is presented. Topics concern the dual resistance to AZT and 3TC, viral resistance to protease inhibitors, and recent laboratory findings on viral resistance patterns that have provided impetus for the design of clinical studies to evaluate rational combinations of protease inhibitors. VX-478, indinavir, and ritonavir study data are presented.

Topics: Antiviral Agents; Carbamates; CD4 Lymphocyte Count; Drug Resistance, Microbial; Furans; HIV; HIV Infections; HIV Protease Inhibitors; Humans; Indinavir; Isoquinolines; Lamivudine; Pyridines; Quinolines; Ritonavir; Saquinavir; Sulfonamides; Thiazoles; Valine; Viremia; Zalcitabine; Zidovudine