Showing papers on "Zidovudine published in 1998"
TL;DR: Although the introduction of protease inhibitors has changed management of HIV infection drastically, this cerebro-protective property will assert the role of these nucleo-side RT inhibitors (NRTI) as a cornerstone ofantiretroviral therapy.
Abstract: After zidovudine (ZDV), a 3′-azido analogue of thymi-dine, was found to be an effective antiretroviral drugagainst HIV [1,2], other nucleoside analogues inhibit-ing reverse transcriptase (RT) soon followed: didano-sine (ddI), zalcitabine (ddC), lamivudine (3TC),stavudine (D4T), and recently abacavir (1592U89)[3–7]. These drugs have demonstrated efficacy inreduction of morbidity and mortality, especially incombination therapy [8–10]. A special feature of someof these drugs is the protection against AIDS dementiacomplex, which appears to be related to good penetra-tion of the blood–brain barrier [11–13]. Although theintroduction of protease inhibitors has changed themanagement of HIV infection drastically, this cerebro-protective property will assert the role of these nucleo-side RT inhibitors (NRTI) as a cornerstone ofantiretroviral therapy [9,10].More than 10 years of experience with NRTI therapyhas revealed important adverse effects ranging frommild (myopathy) to fatal in some cases (pancreatitis,liver failure and lactic acidosis). Behind most of theseside-effects there appears to be a common mechanism:a decreased mitochondrial energy-generating capacity.In this review we will summarize the literature inwhich this mechanism is analysed and will emphasizethe importance of acquired mitochondrial dysfunctionthat will accumulate during long-term treatment withantiretroviral nucleoside analogues.
888 citations
TL;DR: The HIV-infected individuals who receivedInitial therapy with regimens including stavudine or lamivudine had significantly lower mortality and longer AIDS-free survival than those who received initial therapy withregimens limited to zidovudine, didanosine, and zalcitabine.
Abstract: Context.—Clinical trials have established the efficacy of antiretroviral therapy
with double- and triple-drug regimens for individuals infected with the human
immunodeficiency virus (HIV), but the effectiveness of these regimens in the
population of patients not enrolled in clinical trials is unknown.Objective.—To characterize survival following the initiation of antiretroviral
therapy among HIV-infected individuals in the province of British Columbia.Design.—Prospective, population-based cohort study of patients with antiretroviral
therapy available free of charge (median follow-up, 21 months).Setting.—Province of British Columbia, Canada.Patients.—All HIV-positive men and women 18 years of age or older in the province
who were first prescribed any antiretroviral therapy between October 1992
and June 1996 and whose CD4+ cell counts were less than 0.350×109/L.Main Outcome Measures.—Rates of progression from initiation of antiretroviral therapy to death
or a primary acquired immunodeficiency syndrome (AIDS) diagnosis for subjects
who initially received zidovudine-, didanosine-, or zalcitabine-based therapy
(ERA-I) and for those who initially received therapy regimens including lamivudine
or stavudine (ERA-II).Results.—A total of 1178 patients (951 ERA-I, 227 ERA-II) were eligible. A total
of 390 patients died (367 ERA-I, 23 ERA-II), yielding a crude mortality rate
of 33.1%. ERA-I group subjects were almost twice as likely to die as ERA-II
group subjects, with a mortality risk ratio of 1.86 (95% confidence interval
[CI], 1.21-2.86; P=.005). After adjusting for Pneumocystis carinii and Mycobacterium
avium prophylaxis use, AIDS diagnosis, CD4+ cell count,
sex, and age, ERA-I participants were 1.93 times (95% CI, 1.25-2.97; P=.003) more likely to die than ERA-II participants. Among
patients without AIDS when treatment was started, ERA-I participants were
2.50 times (95% CI, 1.59-3.93; P<.001) more likely
to progress to AIDS or death than ERA-II participants.Conclusion.—The HIV-infected individuals who received initial therapy with regimens
including stavudine or lamivudine had significantly lower mortality and longer
AIDS-free survival than those who received initial therapy with regimens limited
to zidovudine, didanosine, and zalcitabine.
867 citations
TL;DR: In this paper, the authors compared the virologic effects of various combinations of nevirapine, didanosine, and zidovudine for sustained suppression of HIV-1 RNA.
Abstract: Context.—Current guidelines recommend that individuals infected with the human
immunodeficiency virus type 1 (HIV-1) be treated using combinations of antiretroviral
agents to achieve sustained suppression of viral replication as measured by
the plasma HIV-1 RNA assay, in the hopes of achieving prolonged remission
of the disease. However, until recently, many drug combinations have not led
to sustained suppression of HIV-1 RNA.Objective.—To compare the virologic effects of various combinations of nevirapine,
didanosine, and zidovudine.Design.—Double-blind, controlled, randomized trial.Setting.—University-affiliated ambulatory research clinics in Italy, the Netherlands,
Canada, and Australia (INCAS).Patients.—Antiretroviral therapy–naive adults free of the acquired immunodeficiency
syndrome with CD4 cell counts between 0.20 and 0.60×109/L
(200-600/µL).Intervention.—Patients received zidovudine plus nevirapine (plus didanosine placebo),
zidovudine plus didanosine (plus nevirapine placebo), or zidovudine plus didanosine
plus nevirapine.Main Outcome Measure.—Plasma HIV-1 RNA.Results.—Of the 153 enrolled patients, 151 were evaluable. At week 8, plasma
HIV-1 RNA levels had decreased by log 2.18, 1.55, and 0.90 in the triple drug
therapy, zidovudine plus didanosine, and zidovudine plus nevirapine groups,
respectively (P<.05). The proportions of patients
with plasma HIV-1 RNA levels below 20 copies per milliliter at week 52 were
51%, 12%, and 0% in the triple drug therapy, zidovudine plus didanosine, and
zidovudine plus nevirapine groups, respectively (P<.001).
Viral amplification was attempted in 59 patients at 6 months. Viral isolation
was unsuccessful in 19 (79%) of 24, 10 (53%) of 19, and 5 (31%) of 16 patients
in the triple drug therapy, zidovudine plus didanosine, and zidovudine plus
nevirapine groups, respectively. Among patients from whom virus could be amplified,
resistance to nevirapine was found in all 11 patients receiving zidovudine
plus nevirapine and in all 5 patients receiving triple drug therapy. Rates
of disease progression or death were 23% (11/47), 25% (13/53), and 12% (6/51)
for the zidovudine plus nevirapine, zidovudine plus didanosine, and triple
drug therapy groups, respectively (P=.08).Conclusions.—Triple drug therapy with zidovudine, didanosine, and nevirapine led
to a substantially greater and sustained decrease in plasma viral load than
the 2-drug regimens studied. Our results also suggest that suppression of
viral replication, as demonstrated by a decrease in the plasma HIV-1 RNA load
below the level of quantitation of the most sensitive test available, may
at least forestall the development of resistance.
742 citations
TL;DR: Unless this topic is appropriately addressed, the likelihood is that drug-resistant variants of HIV, if able to successfully replicate, will sustain the epidemic and limit the effectiveness of antiviral therapy.
Abstract: Widespread use of antiretroviral agents and increasing occurrence of
human immunodeficiency virus (HIV) strains resistant to these drugs have given
rise to a number of important issues. Some of these concerns are distinct
from the obvious question of the relationship between drug resistance and
treatment failure and have potentially widespread public health implications.
The relevant issues include but are not limited to the following:(1) frequency
with which drug-resistant virus may be transmitted via sexual, intravenous,
or mother-to-child routes; (2) ability of drug-resistant variants to be transmitted,
a question that relates, in part, to the relative fitness of such strains;
(3) effectiveness of antiviral therapy in diminishing viral burden in both
blood and genital secretions, and whether this may be compromised in persons
harboring resistant virus; and (4) importance of patient adherence to antiviral
therapy and its relationship to sustained reduction in viral load to minimize
the appearance in and transmission of drug-resistant virus from both blood
and genital secretions. Thus, prevention of both development of HIV drug resistance
as well as transmission of drug-resistant variants is a central issue of public
health importance. Unless this topic is appropriately addressed, the likelihood
is that drug-resistant variants of HIV, if able to successfully replicate,
will sustain the epidemic and limit the effectiveness of antiviral therapy.
506 citations
TL;DR: These results confirm the efficacy of zidovudine prophylaxis and suggest that there are reductions in the rates of perinatal transmission of HIV even with the use of abbreviated regimens that are begun intra partum or in the first 48 hours of life.
Abstract: Background The Pediatric AIDS Clinical Trials Group Protocol 076 reported a reduction in the rate of perinatal transmission of the human immunodeficiency virus (HIV) from 25.5 percent to 8.3 percent with a three-part regimen of zidovudine given ante partum, intra partum, and to the newborn. We examined the effects of abbreviated zidovudine regimens on perinatal HIV transmission using data from the HIV polymerase-chain-reaction (PCR) testing service of the New York State Department of Health. Pregnant women who received abbreviated regimens rather than the recommended regimens did so because of limited prenatal care or by choice. Methods The requisition form used by the PCR testing service included information on the demographic characteristics of the infants and the timing of any perinatal treatment with zidovudine. We also analyzed data on the timing of zidovudine prophylaxis collected by chart review in a subgroup of 454 infants as a means of validating the results in the entire cohort. Results From Aug...
479 citations
TL;DR: Dysregulated immune activation was partially corrected by this regimen; however, the perturbed expression of T cell receptor V regions in the CD4 and CD8 T lymphocyte populations was not significantly affected.
Abstract: Human immunodeficiency virus (HIV)-1 infection is associated with progressive cell-mediated immune deficiency and abnormal immune activation. Although highly active antiretroviral therapy regimens can increase circulating CD4 T lymphocyte counts and decrease the risk of opportunistic complications, the effects of these treatments on immune reconstitution are not well understood. In 44 persons with moderately advanced HIV-1 infection, after 12 weeks of treatment with zidovudine, lamivudine, and ritonavir, plasma HIV-1 RNA fell a median of 2.3 logs (P < .0001). Circulating numbers of naive and memory CD4 T lymphocytes (P < .001), naive CD8 T lymphocytes (P < .004), and B lymphocytes (P < .001) increased. Improved lymphocyte proliferation to certain antigens and a tendency to improvement in delayed-type hypersensitivity also were seen. Dysregulated immune activation was partially corrected by this regimen; however, the perturbed expression of T cell receptor V regions in the CD4 and CD8 T lymphocyte populations was not significantly affected. Ongoing studies will ascertain if longer durations of virus suppression will permit more complete immune restoration.
439 citations
TL;DR: It is proposed that HIV-1 resistance to AZT results from the selectively decreased binding of AZTTP and the increased pyroph phosphorolytic cleavage of chain-terminated viral DNA by the mutant RT at physiological pyrophosphate levels, resulting in a net decrease in chain termination.
Abstract: The multiple mutations associated with high-level AZT resistance (D67N, K70R, T215F, K219Q) arise in two separate subdomains of the viral reverse transcriptase (RT), suggesting that these mutations may contribute differently to overall resistance. We compared wild-type RT with the D67N/K70R/T215F/K219Q, D67N/K70R, and T215F/K219Q mutant enzymes. The D67N/K70R/T215F/K219Q mutant showed increased DNA polymerase processivity; this resulted from decreased template/primer dissociation from RT, and was due to the T215F/K219Q mutations. The D67N/K70R/T215F/K219Q mutant was less sensitive to AZTTP (IC50 approximately 300 nM) than wt RT (IC50 approximately 100 nM) in the presence of 0.5 mM pyrophosphate. This change in pyrophosphate-mediated sensitivity of the mutant enzyme was selective for AZTTP, since similar Km values for TTP and inhibition by ddCTP and ddGTP were noted with wt and mutant RT in the absence or in the presence of pyrophosphate. The D67N/K70R/T215F/K219Q mutant showed an increased rate of pyrophosphorolysis (the reverse reaction of DNA synthesis) of chain-terminated DNA; this enhanced pyrophosphorolysis was due to the D67N/K70R mutations. However, the processivity of pyrophosphorolysis was similar for the wild-type and mutant enzymes. We propose that HIV-1 resistance to AZT results from the selectively decreased binding of AZTTP and the increased pyrophosphorolytic cleavage of chain-terminated viral DNA by the mutant RT at physiological pyrophosphate levels, resulting in a net decrease in chain termination. The increased processivity of viral DNA synthesis may be important to enable facile HIV replication in the presence of AZT, by compensating for the increased reverse reaction rate.
348 citations
TL;DR: The suppression of plasma HIV RNA after six months of treatment with indinavir, zidovudine, and lamivudine is better sustained by the continuation of these three drugs than by maintenance therapy with either indinavIR alone or zidovo-resistance mutations in HIV RNA at base line.
Abstract: Background Combination antiretroviral therapy with indinavir, zidovudine, and lamivudine can suppress the level of human immunodeficiency virus (HIV) RNA in plasma below the threshold of detection for two years or more. We investigated whether a less intensive maintenance regimen could sustain viral suppression after an initial response to combination therapy. Methods HIV-infected subjects who had CD4 cell counts greater than 200 per cubic millimeter, who had been treated with indinavir, lamivudine, and zidovudine, and who had less than 200 copies of HIV RNA per milliliter of plasma after 16, 20, and 24 weeks of induction therapy were randomly assigned to receive either continued triple-drug therapy (106 subjects), indinavir alone (103 subjects), or a combination of zidovudine and lamivudine (107 subjects). The primary end point was loss of viral suppression, which was defined as a plasma level of at least 200 copies of HIV RNA per milliliter on two consecutive measurements during maintenance therapy. Res...
318 citations
TL;DR: Cytarabine administered either intravenously or intrathecally does not improve the prognosis of HIV-infected patients with progressive multifocal leukoencephalopathy who are treated with the antiretroviral agents, nor does high-dose antireTroviral therapy alone appear to improve survival over that reported in untreated patients.
Abstract: Background Progressive multifocal leukoencephalopathy affects about 4 percent of patients with the acquired immunodeficiency syndrome (AIDS), and survival after the diagnosis of leukoencephalopathy averages only about three months. There have been anecdotal reports of improvement but no controlled trials of therapy with antiretroviral treatment plus intravenous or intrathecal cytarabine. Methods In this multicenter trial, 57 patients with human immunodeficiency virus (HIV) infection and biopsy-confirmed progressive multifocal leukoencephalopathy were randomly assigned to receive one of three treatments: antiretroviral therapy alone, antiretroviral therapy plus intravenous cytarabine, or antiretroviral therapy plus intrathecal cytarabine. After a lead-in period of 1 to 2 weeks, active treatment was given for 24 weeks. For most patients, antiretroviral therapy consisted of zidovudine plus either didanosine or stavudine. Results At the time of the last analysis, 14 patients in each treatment group had died, ...
306 citations
TL;DR: An interaction between zidovudine prophylaxis and elective cesarean delivery in decreasing transmission of HIV-1 from mother to child is observed, which may have clinical implications for prevention.
Abstract: Context.—It is unclear whether elective cesarean delivery may have a protective
effect against the transmission of human immunodeficiency virus 1 (HIV-1).Objective.—To investigate whether mode of delivery has an impact on perinatal HIV-1
transmission in the presence of zidovudine prophylaxis.Design.—A prospective cohort study.Setting.—The 85 perinatal centers in the French Perinatal Cohort, from 1985 to
1996.Patients.—A total of 2834 singleton children born to mothers with HIV-1 infection.Main Outcome Measure.—Human immunodeficiency virus 1 infection of the infant.Results.—No zidovudine was used in 1917 pregnancies and zidovudine prophylaxis
was used in 902 pregnancies. Cesarean deliveries were performed in 10.9% on
an emergent basis and in 8.3% electively, prior to labor or membrane rupture.
In 1917 mothers who did not receive zidovudine, of 1877 with information on
mode of delivery, 17.2% transmitted HIV-1 to their child. Risk factors statistically
significantly associated with transmission were maternal p24 antigenemia,
cervicovaginal infections during pregnancy, amniotic fluid color, and rupture
of membranes 4 hours or more before delivery. Mode of delivery was not related
to transmission. In 902 mothers receiving zidovudine, transmission was 6.4%
in 872 with information on mode of delivery, and elective cesarean delivery
(n=133) was associated with a lower transmission rate than emergent cesarean
or vaginal delivery (0.8%, 11.4%, and 6.6%, respectively; P=.002). In a multivariate analysis of all mother-child pairs, including
obstetrical risk factors, maternal p24 antigenemia, and zidovudine prophylaxis,
interaction between mode of delivery and zidovudine prophylaxis was significant
(P=.007). In the multivariate analysis of pregnancies
with zidovudine prophylaxis, factors related to transmission rate were maternal
p24 antigenemia, amniotic fluid color, and mode of delivery. Adjusted odds
ratios (95% confidence intervals) were 1.6 (0.7-3.6) for emergent cesarean
delivery and 0.2 (0.0-0.9) for elective cesarean delivery (P=.04) in comparison with vaginal delivery.Conclusions.—We observed an interaction between zidovudine prophylaxis and elective
cesarean delivery in decreasing transmission of HIV-1 from mother to child.
This observation may have clinical implications for prevention.
278 citations
TL;DR: A 3-drug combination of indinavir, zidovudine, and lamivudine started simultaneously has durable antiretroviral activity for at least 2 years and Sequential initiation of the same 3 drugs is much less effective.
Abstract: Context.—Combination antiretroviral therapy can markedly suppress human immunodeficiency
virus (HIV) replication but the duration of HIV suppression varies among patients.Objective.—To compare the antiretroviral effect of a 3-drug regimen started simultaneously
or sequentially in patients with HIV infection.Design.—A multicenter, randomized, double-blind study, modified after at least
24 weeks of blinded therapy to provide open-label 3-drug therapy with follow-up
through 100 weeks.Setting.—Four clinical research unitsPatients.—Ninety-seven patients with HIV infection who had taken zidovudine for
at least 6 months with serum HIV RNA level of at least 20000 copies/mL and
CD4 cell count of 0.05 to 0.40×109/L.Interventions.—Patients were initially randomized to receive 1 of 3 antiretroviral
regimens: indinavir, 800 mg every 8 hours; zidovudine, 200 mg every 8 hours
and lamivudine, 150 mg every 12 hours; or all 3 drugs. After at least 24 weeks
of blinded therapy, all patients received open-label 3-drug therapy.Main Outcome Measures.—Antiretroviral activity was assessed by changes in HIV RNA level and
CD4 cell count from baseline. Data through 100 weeks were summarized.Results.—Simultaneous initiation of indinavir, zidovudine, and lamivudine suppressed
HIV RNA in 78% (25/32) of contributing patients to less than 500 copies/mL
and increased CD4 cell count to a median of 0.209×109/L above
baseline at 100 weeks. When these 3 drugs were initiated sequentially, only
30% to 45% of contributing patients (10 of 33 in the zidovudine-lamivudine
group and 13 of 29 in the indinavir group, respectively) had a sustained reduction
in HIV RNA to less than 500 copies/mL, and median CD4 cell count increased
to 0.101 to 0.163×109/L above baseline at 100 weeks.Conclusions.—A 3-drug combination of indinavir, zidovudine, and lamivudine started
simultaneously has durable antiretroviral activity for at least 2 years. Sequential
initiation of the same 3 drugs is much less effective.
TL;DR: In this article, the authors evaluated the safety of antiretroviral therapy in pregnant women and their newborns through an observational study and found that one or more adverse events occurred in 29 out of 37 women and in 14 out of 30 babies.
Abstract: BACKGROUND: Therapies containing two reverse transcriptase inhibitors (RTI) with or without protease inhibitors are used with increasing frequency in pregnant HIV-infected women. OBJECTIVE: To assess the safety of antiretroviral therapy in pregnant women and their newborns. METHODS: All clinical events and laboratory abnormalities in pregnant women on RTI with or without protease inhibitors and in their newborns were collected through an observational study. RESULTS: A total of 37 HIV-infected pregnant women have given birth to 30 children (by 30 April 1998). All received RTI, which were combined with protease inhibitors in 16 cases. Twelve women became pregnant while on treatment. Drugs used were as follows: zidovudine (n = 33), lamivudine (n = 33), stavudine (n = 4), indinavir (n = 9), ritonavir (n = 4), nelfinavir (n = 2) and saquinavir (n = 2). Adverse events during pregnancy were anaemia (n = 15), elevation of transaminases (n = 4), nausea/vomiting (n = 4), glucose intolerance (n = 2), nephrolithiasis (n = 2), diarrhoea (n = 2), hypertension (n = 1), insulin-requiring diabetes (n = 1). Adverse events in neonates were prematurity (n = 10), anaemia (n = 8), cutaneous angioma (n = 2), cryptorchidism (n = 2), transient hepatitis (n = 1). Non-life-threatening intracerebral haemorrhage occurred in a premature baby (33 weeks gestation) exposed during fetal life to zidovudine-lamivudine-indinavir, and in a term baby exposed to stavudine-lamivudine-indinavir. Extrahepatic biliary atresia occurred in one newborn exposed to zidovudine-lamivudine-indinavir. Maternal viral load was below 400 copies/ml in 18 out of 30 patients who delivered. One case of mother-to-child HIV transmission was identified. CONCLUSIONS: In HIV-infected pregnant women treated with two RTI with or without protease inhibitors, one or more adverse events occurred in 29 out of 37 women and in 14 out of 30 babies. In newborns, frequent prematurity, one case of biliary malformation and one intracerebral haemorrhage in a term baby are of concern. These observations do not preclude combination therapies during pregnancy but emphasize the necessity to maintain updated registers on their safety.
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TL;DR: In this paper, Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) which shows good inhibitory activity against HIV-1.
Abstract: ▴ Efavirenz is a non-nucleoside reverse transcriptase inhibitor (NNRTI) which shows good inhibitory activity against HIV-1.
▴ Reduced susceptibility to efavirenz has been reported with HIV-1 variants containing single and multiple mutations to the reverse transcriptase enzyme. In vitro and in vivo data suggest that the resistance profile of efavirenz overlaps with that of the NNRTIs nevirapine and delavirdine.
▴ Clinically significant drug interactions have been reported with efavirenz and indinavir and saquinavir. An increase in dosage of indinavir from 800 to 1000mg 3 times daily is recommended during coadministration with efavirenz. Use of efavirenz in combination with saquinavir as the sole protease inhibitor is not recommended.
▴ Once-daily efavirenz in combination with zidovudine plus lamivudine or indinavir or nelfinavir increased CD4+ cell counts and reduced HIV RNA plasma levels to below quantifiable levels (<400 copies/m1) in HIV-infected patients. A sustained reduction in viral load was maintained for at least 72 weeks in 1 study.
▴ Nervous system symptoms (including headache, dizziness, insomnia and fatigue) and dermatological effects (including maculopapular rash) appear to be the most common adverse events reported with efavirenz-containing antiretroviral regimens.
TL;DR: It is argued that HIV replication differs significantly between patients on potent antiretroviral therapy with low but detectable viral loads and those with undetectable viral loads.
Abstract: Potent antiretroviral therapy can reduce human immunodeficiency virus (HIV) in plasma to levels below the limit of detection for up to 2 years, but the extent to which viral replication is suppressed is unknown. To search for ongoing viral replication in 10 patients on combination antiretroviral therapy for up to 1 year, the emergence of genotypic drug resistance across different compartments was studied and correlated with plasma viral RNA levels. In addition, lymph node (LN) mononuclear cells were assayed for the presence of multiply spliced RNA. Population sequencing of HIV-1 pol was done on plasma RNA, peripheral blood mononuclear cell (PBMC) RNA, PBMC DNA, LN RNA, LN DNA, and RNA from virus isolated from PBMCs or LNs. A special effort was made to obtain sequences from patients with undetectable plasma RNA, emphasizing the rapidly emerging lamivudine-associated M184V mutation. Furthermore, concordance of drug resistance mutations across compartments was investigated. No evidence for viral replication was found in patients with plasma HIV RNA levels of <20 copies/ml. In contrast, evolving genotypic drug resistance or the presence of multiply spliced RNA provided evidence for low-level replication in subjects with plasma HIV RNA levels between 20 and 400 copies/ml. All patients failing therapy showed multiple drug resistance mutations in different compartments, and multiply spliced RNA was present upon examination. Concordance of nucleotide sequences from different tissue compartments obtained concurrently from individual patients was high: 98% in the protease and 94% in the reverse transcriptase regions. These findings argue that HIV replication differs significantly between patients on potent antiretroviral therapy with low but detectable viral loads and those with undetectable viral loads.
TL;DR: In HIV-1-infected adults not previously treated with antiretroviral drugs whose plasma HIV- 1 RNA levels fell below 500 copies per milliliter after three months of induction therapy with zidovudine, lamivUDine, and indinavir, two-drug maintenance therapy was less effective in sustaining a reduced viral load than continued three-drug therapy.
Abstract: Background The long-term effectiveness of potent three-drug antiretroviral regimens for the treatment of human immunodeficiency virus type 1 (HIV-1) infection is limited by problems related to compliance and tolerability. We investigated whether two-drug maintenance therapy would suppress viral replication after a three-month period of aggressive triple-drug induction therapy. Methods A total of 378 HIV-1–infected adults who had not received previous antiretroviral treatment received three months of induction therapy consisting of 300 mg of zidovudine every 12 hours, 150 mg of lamivudine every 12 hours, and 800 mg of indinavir every 8 hours. The 279 patients in whom the plasma HIV-1 RNA titer fell below 500 copies per milliliter after two months of triple-drug therapy, and who completed the induction phase, were randomly assigned at month 3 to one of the following three open-label maintenance regimens: zidovudine, lamivudine, and indinavir; zidovudine and lamivudine; or zidovudine and indinavir. The prima...
TL;DR: Viral RNA determinations at intermediate timepoints may be prognostic of impending virologic failure of protease inhibitor therapy and strategies that allow intensification of initial antiretroviral regimens in the subset of patients with incomplete virological response should be investigated.
Abstract: Objective: To determine markers that are associated with the durability of virologic response to therapy with HIV protease inhibitors in HIV-infected individuals. Design: This study encompassed two retrospective analyses of the duration of virologic response to protease inhibitor therapy. The first analysis included 29 patients receiving either monotherapy or combination therapy with the protease inhibitor ritonavir whose plasma HIV RNA levels rebounded from the point of greatest decline with mutations associated with resistance to ritonavir. The second analysis included a cohort of 102 patients who initially responded to randomized treatment with either monotherapy with ritonavir or combination therapy with ritonavir and zidovudine. Methods: Durability of response was defined as the time from the initiation of therapy to the point at which plasma HIV RNA displayed a sustained increase of at least 0.6 log 10 copies/ml from the nadir value. In the first analysis, durability of response was analyzed with respect to baseline HIV RNA, HIV RNA at the nadir, and the drop in HIV RNA from baseline to the nadir. In the second analysis, time to rebound was examined using Kaplan-Meier analysis, stratifying by either baseline HIV RNA or HIV RNA at the nadir. Results: In both analyses, the durability of response was not highly associated with either baseline RNA or the magnitude of RNA decline from baseline. Instead, a strong relationship was observed between the durability of response and the nadir plasma HIV-1 RNA value (P < 0.01). The nadir in viral load was generally reached after 12 weeks of randomized therapy. Conclusions: Viral RNA determinations at intermediate timepoints may be prognostic of impending virologic failure of protease inhibitor therapy. Therapeutic strategies that allow intensification of initial antiretroviral regimens in the subset of patients with incomplete virological response before the emergence of high level resistance should be investigated.
TL;DR: Elective Cesarean section and zidovudine prophylaxis appear to have an additive effect in the prevention of vertical HIV transmission.
Abstract: To study the effect of elective Cesarean section and zidovudine prophylaxis on vertical HIV transmission.
TL;DR: Dietary supplements with vitamins C and E at supranutritional doses protect against oxidative damage to skeletal muscle mitochondria caused by AZT.
Abstract: AIDS patients who receive zidovudine (AZT) frequently suffer from myopathy. This has been attributed to mitochondrial (mt) damage, and specifically to the loss of mtDNA. This study examines whether AZT causes oxidative damage to DNA in patients and to skeletal muscle mitochondria in mice, and whether this damage may be prevented by supranutritional doses of antioxidant vitamins. Asymptomatic HIV-infected patients treated with AZT have a higher urinary excretion (355+/-100 pmol/kg/d) of 8-oxo-7, 8-dihydro-2'-deoxyguanosine (8-oxo-dG) (a marker of oxidative damage to DNA) than untreated controls (asymptomatic HIV-infected patients) (182+/-29 pmol/kg/d). This was prevented (110+/-79 pmol/kg/d) by simultaneous oral treatment with AZT plus antioxidant vitamins (C and E). Mice treated with AZT also had a significantly higher urinary excretion of 8-oxo-dG than controls. Skeletal muscle mtDNA of mice treated with AZT had more 8-oxo-dG than controls. mt lipoperoxidation was also increased and skeletal muscle glutathione was oxidized. These effects may be due to an increased peroxide production by muscle mitochondria of AZT-treated animals. Dietary supplements with vitamins C and E at supranutritional doses protect against oxidative damage to skeletal muscle mitochondria caused by AZT.
TL;DR: In this article, triple combination treatment of HIV-1 infection using two reverse transcriptase inhibitors and a protease inhibitor can result in significant and sustained decreases in the quantity of viral RNA in peripheral blood.
Abstract: Objectives: Triple combination treatment of HIV-1 infection using two reverse transcriptase inhibitors and a protease inhibitor can result in significant and sustained decreases in the quantity of viral RNA in peripheral blood. Lymphoid tissue, however, constitutes the major reservoir of HIV in infected patients. Study of the viral burden in these tissues has provided additional insight in the efficacy of antiretroviral treatment. Design: Patients were randomized into two groups in order to study differences in the development of resistance to reverse transcriptase inhibitors. Group I started treatment with all three drugs simultaneously. Group II started with ritonavir monotherapy, aiming at initial reduction in virus production before the addition of lamivudine and zidovudine 3 weeks later. Methods: Changes in the amount of HIV in plasma and tonsillar lymphoid tissue during 24 weeks of treatment with ritonavir, lamivudine and zidovudine were studied by reverse transcriptase polymerase chain reaction. Results: Thirty-three antiretroviral-naive HIV-infected patients were included for analysis. After 24 weeks, median CD4+ cell count increased by 152 x 10 6 /l and median plasma viral RNA levels decreased by at least 2.87 log 10 copies/ml. In 88% of the patients remaining on treatment, plasma RNA levels were below the quantification limit of the assay used (mean, 2.4 log 10 copies/ml). The lymphoid tissue viral burden, ranging from 9.16 to 8.52 log 10 copies/g at baseline, was markedly reduced with at least 2.1 log 10 copies/g by week 24 in the five patients analysed. Eight patients (24%) withdrew because of side-effects. In one patient in group II, ritonavir and lamivudine resistance-associated mutations developed. Conclusions: Treatment with this triple antiretroviral drug combination produced a durable and strong decrease of HIV-1 RNA burden in both plasma and lymphoid tissue.
TL;DR: Insight is provided into competition among multiple HIV-1 variants, which likely occurs in vivo with drug selection pressure, and may be applicable in more complex mathematical models for predicting the emergence of HIV- 1 variants after the initiation of antiretroviral therapy.
Abstract: Replication of mixtures of two or more human immunodeficiency virus type 1 (HIV-1) variants would be expected to result in the eventual selection of the fittest virus due to Darwinian competition among the variants. The relative proportions of known HIV-1 variants (which may differ only by a single nucleotide from a standard "wild-type" virus, HIV-1HXB2) in mixed viral cultures were quantified by analysis of automated sequence signals of reverse transcriptase PCR products. With this method, the relative levels of replicative fitness of several zidovudine (3'-azidothymidine)-resistant HIV-1HXB2 variants were estimated under controlled in vitro conditions by measuring the rate of change in the proportions of viral variants as they replicated in cell cultures both in the presence and in the absence of drug selection pressure. These variants were engineered to contain commonly observed zidovudine resistance mutations in the HIV-1 reverse transcriptase (M41L, K70R, T215Y, and M41L+T215Y). In the absence of zidovudine, all variants tested displayed reduced replicative fitness compared to wild-type HIV-1HXB2. The order of relative fitness was wild type > K70R >> T215Y = M41L+T215Y > M41L. Mixed cultures in the presence of zidovudine showed a dose-dependent selection pressure against the wild-type virus which varied according to the resistance profile of each virus. The information gathered from this approach provides insight into competition among multiple HIV-1 variants, which likely occurs in vivo with drug selection pressure, and may be applicable in more complex mathematical models for predicting the emergence of HIV-1 variants after the initiation of antiretroviral therapy.
TL;DR: Lamivudine and zidovudine pharmacokinetics in pregnant women were similar to those in nonpregnant adults and neonates and all neonates had HIV-1 RNA levels below the limit of quantification at birth and at ages 1 and 2 weeks.
Abstract: The safety, pharmacokinetics, and antiretroviral activity of lamivudine alone and in combination with zidovudine was studied in pregnant women infected with human immunodeficiency virus type 1 (HIV-1) and their neonates. Women received the drugs orally from week 38 of pregnancy to 1 week after delivery. Neonate therapy began 12 h after delivery and continued for 1 week. Both treatment regimens were well-tolerated in women and newborns. Lamivudine and zidovudine pharmacokinetics in pregnant women were similar to those in nonpregnant adults. Lamivudine and zidovudine freely crossed the placenta and were secreted in breast milk. Neonatal lamivudine clearance was about half that in pediatric patients; zidovudine clearance was consistent with previous reports. HIV-1 RNA could be quantified in 17 of the 20 women. At the onset of labor/delivery, mean virus load had decreased by approximately 1.5 log10 copies/mL in both treatment cohorts. Although not definitive for HIV-1 infection status, all neonates had HIV-1 RNA levels below the limit of quantification at birth and at ages 1 and 2 weeks.
TL;DR: It is found that time-dependent cerebrospinal-fluid to plasma drug-penetration ratios, which were highest for zidovudine followed by stavudine and lamivudine, might be useful in the prevention of AIDS dementia complex.
TL;DR: Maternal samples were assessed from 96 women enrolled in Pediatric AIDS Clinical Trials Group protocol 076 to determine the prevalence of human immunodeficiency virus type 1 (HIV-1) genotypic zidovudine resistance at entry, and the role of zidovsky resistance in vertical transmission of HIV-1 despite zidvudine therapy.
Abstract: Maternal samples were assessed from 96 women enrolled in Pediatric AIDS Clinical Trials Group protocol 076 to determine the prevalence of human immunodeficiency virus type 1 (HIV-1) genotypic zidovudine resistance at entry, if zidovudine resistance developed on study, and the role of zidovudine resistance in vertical transmission of HIV-1 despite zidovudine therapy. Low and high levels of genotypic resistance were assessed by differential hybridization, oligoligation, or direct sequencing of plasma HIV-1 RNA for codons K70R and T215Y/F. None of the women had high-level genotypic resistance to zidovudine at study entry or delivery. For low-level zidovudine resistance, the 95% confidence intervals were 0.3%-6.8% for baseline prevalence and 0.3%-14% for delivery incidence. Low-level zidovudine resistance, adjusted for plasma viral RNA level at delivery, was not strongly associated with an increase in vertical transmission risk (odds ratio, 4.8; 95% confidence interval, 0.2-131; P = .35).
TL;DR: The apparent ability of nevirapine to readily permeate the BBB and enter the brain, where it may inhibit replication of HIV, potentially increases its therapeutic value.
TL;DR: Perinatal HIV transmission risk has declined with increasing perinatal zidovudine use and changes in other factors, and further reduction in transmission may be possible by reducing the incidence of other potentially modifiable risk factors, such as long duration of membrane rupture and prematurity.
Abstract: Objectives: To evaluate the impact of perinatal zidovudine use on the risk of perinatal transmission of HIV and to determine risk factors for transmission among women using perinatal zidovudine. Design: Prospective cohort study of 1533 children born to HIV-infected women between 1985 and 1995 in four US cities. Methods: The association of potential risk factors with perinatal HIV transmission was assessed with univariate and multivariate statistics. Results: The overall transmission risk was 18% [95%, confidence interval (CI), 16-21]. Factors associated with transmission included membrane rupture > 4 h before delivery [retentive risk (RR), 2.1; 95% Cl, 1.6-2.7], gestational age < 37 weeks (RR, 1.8; 95% Cl, 1.4-2.2), maternal CD4+ lymphocyte count < 500 x 10 6 cells/l (RR, 1.7; 95% Cl, 1.3-2.2), birthweight < 2500 g (RR, 1.7; 95% CI, 1.3-2.1), and antenatal and neonatal zidovudine use (RR, 0.6; 95% CI, 0.4-0.9). For infants exposed to zidovudine antenatally and neonatally, the transmission risk was 13% overall but was significantly lower following shorter duration of membrane rupture (7%) and term delivery (9%). The transmission risk declined from 22% before 1992 to 11% in 1995 (P < 0.001) in association with increasing zidovudine use and changes in other risk factors. Conclusions: Perinatal HIV transmission risk has declined with increasing perinatal zidovudine use and changes in other factors. Further reduction in transmission for women taking zidovudine may be possible by reducing the incidence of other potentially modifiable risk factors, such as long duration of membrane rupture and prematurity.
TL;DR: In this article, a site-directed mutagenesis experiment was conducted to determine the genetic basis of dual resistance to both AZT and 3TC in the context of reverse transcriptase (RT) mutations.
Abstract: Zidovudine (3′-azido-3′-doexythymidine, AZT, or Retrovir) is commonly used in combination with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. AZT therapy delays the development of AIDS and increases the survival of patients with AIDS (6, 12, 39). Long-term treatment with AZT monotherapy results in the eventual development of resistance to AZT (22, 26, 33), which ultimately leads to treatment failure (4, 32). Site-directed mutagenesis experiments have demonstrated that at least five amino acid changes in reverse transcriptase (RT) of HIV-1 (at codons 41, 67, 70, 215, and 219) are responsible for AZT resistance (16, 20; for reviews, see references 19 and 31). The first mutation to arise after several months of AZT monotherapy is typically at codon 70, which results in an approximate eightfold increase in the 50% inhibitory concentration (IC50). More resistant viruses, usually having combinations of mutations that include changes at codons 41 and 215, subsequently become dominant in the resistant virus population (3, 17). Highly AZT-resistant variants (with IC50s increased more than 100-fold) require the accumulation of four to six mutations in RT, frequently including a recently recognized mutation at codon 210 of RT (10, 11).
In contrast to AZT resistance, high-level resistance to the nucleoside analog l-2′,3′-dideoxy-3′-thiacytidine (3TC or lamivudine) is conferred by a single mutation in HIV-1 RT at codon 184 (Met-184 to Val or occasionally Ile) (2, 7, 34, 38). The appearance of this mutation during 3TC therapy is associated with an increase in plasma HIV-1 levels and treatment failure (35). Of note is that the 184 Val mutation causes a concomitant increase in AZT sensitivity in genotypically AZT-resistant backgrounds (2, 24, 38). Furthermore, AZT-3TC combination therapy in drug-naive patients leads to a delay in the appearance of AZT resistance mutations even though 3TC resistance occurs rapidly (18, 24). These observations have prompted speculation that dual resistance to both drugs may not develop easily, as phenotypic AZT resistance in the presence of the 184 Val mutation may be rare.
The results of several clinical trials examining the safety and efficacy of AZT-3TC combination therapy have recently been published (1, 5, 14, 37). Collectively, these studies showed substantial effects on virological markers and significant clinical benefit in either therapy-naive or AZT-experienced patients. One plausible explanation for the duration of this benefit in therapy-naive patients is the observed delay in the development of AZT resistance, as discussed above. In AZT-experienced patients, more complex patterns of virological response and resistance have been observed, ranging from restoration of AZT susceptibility to the development of AZT-3TC dual resistance (13, 27, 28).
An HIV-1 variant that was selected in cell culture and that became simultaneously highly resistant to AZT and 3TC was recently described (8). This mutant was obtained by cell culture passage in both AZT and 3TC of a preexisting highly AZT-resistant clinical isolate (1373). To increase our understanding of how HIV-1 can become resistant to both AZT and 3TC, we describe a mapping and site-directed mutagenesis study designed to define the genetic basis of dual resistance of this cell culture-selected variant. A novel polymorphism at RT codon 333 was shown to be responsible for facilitating dual resistance in the context of AZT and 3TC resistance mutations. To determine the relevance of this codon 333 polymorphism in AZT- and 3TC-treated patients, we studied HIV-1 clinical isolates by genetic mapping of RT molecular clones. In some cases, polymorphism at codon 333 was responsible for facilitating dual resistance.
TL;DR: S-1153 shows a significant accumulation in lymph nodes, where most HIV-1 infection is thought to occur, and may be an appropriate candidate for two- to three-drug combination therapy for HIV infection.
Abstract: S-1153 is a new imidazole compound that inhibits human immunodeficiency virus (HIV) type 1 (HIV-1) replication by acting as a nonnucleoside reverse transcriptase inhibitor (NNRTI). This compound inhibits replication of HIV-1 strains that are resistant to nucleoside and nonnucleoside reverse transcriptase inhibitors. S-1153 has a 50% effective concentration in the range of 0.3 to 7 ng/ml for strains with single amino acid substitutions that cause NNRTI resistance, including the Y181C mutant, and also has potent activity against clinical isolates. The emergence of S-1153-resistant variants is slower than that for nevirapine, and S-1153-resistant variants contained at least two amino acid substitutions, including F227L or L234I. S-1153-resistant variants are still sensitive to the nucleoside reverse transcriptase inhibitors zidovudine (AZT) and lamivudine. In a mouse and MT-4 (human T-cell line) in vivo HIV replication model, S-1153 and AZT administered orally showed a marked synergy for the inhibition of HIV-1 replication. S-1153 shows a significant accumulation in lymph nodes, where most HIV-1 infection is thought to occur. S-1153 may be an appropriate candidate for two- to three-drug combination therapy for HIV infection.
Journal Article•
TL;DR: AZT inhibited the growth of all tumoral cell lines, but it did so in a wide range of concentrations, and inhibited colony formation in soft agar and telomerase activity.
Abstract: The effect of zidovudine (3'-azido-3'-deoxythymidine; AZT) was investigated in four breast cancer cell lines, a T4 cell leukemia, and a normal breast cell line in vitro. AZT inhibited the growth of all tumoral cell lines, but it did so in a wide range of concentrations. The growth of a normal breast cell line was also inhibited, although it required a much higher concentration. Furthermore, AZT inhibited colony formation in soft agar and telomerase activity. These results indicated that AZT can be potentially used, alone or in combination, as an anti-breast cancer agent.
TL;DR: The variance in sequence evolution observed among patients, in particular at codon 215, supports a role for chance in the evolution of the RT domain.
Abstract: Sequences of the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) domain were determined by direct sequencing of HIV-1 RNA in successive plasma samples from eight seroconverting patients infected with virus bearing the T215Y/F amino acid substitution associated with zidovudine (ZDV) resistance. At baseline, additional mutations associated with ZDV resistance were detected. Three patients had the M41L amino acid change, which persisted. Two patients had both the D67N and the K70R amino acid substitutions; reversion to the wild type was seen at both positions in one of these patients and at codon 70 in the other one. Reversion to the wild type at codon 215 was observed in only one of eight patients. Unusual amino acids, such as aspartic acid (D) and cysteine (C), appeared at position 215 in four patients during follow-up. These variants isolated by coculturing were sensitive to ZDV. Overgrowth of these variants suggests that they have better fitness than the original T215Y variant. Intraindividual nucleoside substitutions over time were 10 times more frequent in codons associated with ZDV resistance (41, 67, 70, 215, and 219) than in other codons of the RT domain. The predominance of nonsynonymous substitutions observed over time suggests that most changes reflect adaptation of the RT function. The variance in sequence evolution observed among patients, in particular at codon 215, supports a role for chance in the evolution of the RT domain.
TL;DR: Combination therapy with either ZDv/3TC or ZDV/ddI was superior, as determined by clinical and laboratory measures, to monotherapy with ddI.