Carlos Zala

A Pilot Study of Hydroxyurea among Patients with Advanced Human Immunodeficiency Virus (HIV) Disease Receiving Chronic Didanosine Therapy: Canadian HIV Trials Network Protocol 080

To assess the in vivo short-term antiretroviral effect of hydroxyurea in human immunodeficiency virus (HIV)-infected persons chronically treated with didanosine (ddI), 26 patients with CD4 cell counts between 100 and 350 were enrolled in a 12-week, open-label pilot study and randomly assigned to receive 500 or 1000 mg/day hydroxyurea. Clinical status, laboratory toxicities, CD4 lymphocyte count, and HIV RNA plasma virus load were assessed weekly. Median declines from baseline of 0.02 and 0.63 log10 HIV-1 RNA copies/mL of plasma were observed for the 500- and 1000-mg/day groups, respectively (P = .02). CD4 cell counts did not change significantly with the addition of hydroxyurea; however, a small but statistically significant decrease in counts was observed during the washout phase. Both doses of hydroxyurea were well-tolerated. These results demonstrate a substantial decrease in plasma virus load when 1000 mg of hydroxyurea is administered over 1 month as adjunctive therapy to ddI among HIV-infected persons with 100-350 CD4 cells/mm3.

Origin of Human Immunodeficiency Virus Type 1 Quasispecies Emerging after Antiretroviral Treatment Interruption in Patients with Therapeutic Failure

ABSTRACT The emergence of antiretroviral (ARV) drug-resistant human immunodeficiency virus type 1 (HIV-1) quasispecies is a major cause of treatment failure. These variants are usually replaced by drug-sensitive ones when the selective pressure of the drugs is removed, as the former have reduced fitness in a drug-free environment. This was the rationale for the design of structured ARV treatment interruption (STI) studies for the management of HIV-1 patients with treatment failure. We have studied the origin of drug-sensitive HIV-1 quasispecies emerging after STI in patients with treatment failure due to ARV drug resistance. Plasma and peripheral blood mononuclear cell samples were obtained the day of treatment interruption (day 0) and 30 and 60 days afterwards. HIV-1 pol and env were partially amplified, cloned, and sequenced. At day 60 drug-resistant variants were replaced by completely or partially sensitive quasispecies. Phylogenetic analyses of pol revealed that drug-sensitive variants emerging after STI were not related to their immediate temporal ancestors but formed a separate cluster, demonstrating that STI leads to the recrudescence and reemergence of a sequestrated viral population rather than leading to the back mutation of drug-resistant forms. No evidence for concomitant changes in viral tropism was seen, as deduced from env sequences. This study demonstrates the important role that the reemergence of quasispecies plays in HIV-1 population dynamics and points out the difficulties that may be found when recycling ARV therapies with patients with treatment failure.

Immunologic Response to Antiretroviral Therapy in Hepatitis C Virus–Coinfected Adults in a Population-Based HIV/AIDS Treatment Program

BACKGROUND We sought to characterize the impact that hepatitis C virus (HCV) infection has on CD4 cells during the first 48 weeks of antiretroviral therapy (ART) in previously ART-naive human immunodeficiency virus (HIV)-infected patients. METHODS The HIV/AIDS Drug Treatment Programme at the British Columbia Centre for Excellence in HIV/AIDS distributes all ART in this Canadian province. Eligible individuals were those whose first-ever ART included 2 nucleoside reverse transcriptase inhibitors and either a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor and who had a documented positive result for HCV antibody testing. Outcomes were binary events (time to an increase of > or = 75 CD4 cells/mm3 or an increase of > or = 10% in the percentage of CD4 cells in the total T cell population [CD4 cell fraction]) and continuous repeated measures. Statistical analyses used parametric and nonparametric methods, including multivariate mixed-effects linear regression analysis and Cox proportional hazards analysis. RESULTS Of 1186 eligible patients, 606 (51%) were positive and 580 (49%) were negative for HCV antibodies. HCV antibody-positive patients were slower to have an absolute (P<.001) and a fraction (P = .02) CD4 cell event. In adjusted Cox proportional hazards analysis (controlling for age, sex, baseline absolute CD4 cell count, baseline pVL, type of ART initiated, AIDS diagnosis at baseline, adherence to ART regimen, and number of CD4 cell measurements), HCV antibody-positive patients were less likely to have an absolute CD4 cell event (adjusted hazard ratio [AHR], 0.84 [95% confidence interval [CI], 0.72-0.98]) and somewhat less likely to have a CD4 cell fraction event (AHR, 0.89 [95% CI, 0.70-1.14]) than HCV antibody-negative patients. In multivariate mixed-effects linear regression analysis, HCV antibody-negative patients had increases of an average of 75 cells in the absolute CD4 cell count and 4.4% in the CD4 cell fraction, compared with 20 cells and 1.1% in HCV antibody-positive patients, during the first 48 weeks of ART, after adjustment for time-updated pVL, number of CD4 cell measurements, and other factors. CONCLUSION HCV antibody-positive HIV-infected patients may have an altered immunologic response to ART.

Human Immunodeficiency Virus-Infected Persons with Mutations Conferring Resistance to Zidovudine Show Reduced Virologic Responses to Hydroxyurea and Stavudine-Lamivudine

The baseline predictors of poor virologic response (<0.5 log decrease in plasma virus load) were examined in two 1996 pilot trials of combination nucleoside-analogue therapy. One trial examined the addition of hydroxyurea to didanosine therapy; the other examined stavudine-lamivudine in combination. In both, predictors of virologic response included the presence of mutations associated with zidovudine resistance. For hydroxyurea, the odds ratio (OR) of failure to achieve a short-term (4 weeks) virologic response in a bivariate logistic regression model was 30.8 (95% confidence interval [CI], 1.75-543; P=.02) for use of lower dose hydroxyurea (500 mg/day) and 14.7 (95% CI, 1.1-200; P=.04) for the presence of a zidovudine-related mutation. For the stavudine-lamivudine study, the OR of failure to achieve a virologic response at 4 weeks in a multivariate logistic regression model was 23 (95% CI, 2.7-199; P=.004) for the presence of a mutation at codon 215.

Higher rate of toxicity with no increased efficacy when hydroxyurea is added to a regimen of stavudine plus didanosine and nevirapine in primary HIV infection.

Summary: Twenty‐four subjects presenting at a single treatment center with primary HIV infection were enrolled in a pilot study aimed to establish the possible role of hydroxyurea in this setting. Study participants were randomly assigned to receive or not to receive hydroxyurea in addition to stavudine (d4T) plus didanosine (ddI) and nevirapine (NVP). Seventy‐five percent of patients without hydroxyurea had plasma HIV RNA below 50 copies/mL at 48 weeks by both intention‐to‐treat (ITT) and on‐treatment (OT) analysis in comparison with 50% (ITT) and 67% (OT) of patients with hydroxyurea (p > .1). A median increase of >200 cells/mm3 was observed from baseline to week 48 whether or not hydroxyurea was included in the regimen. Overall, in 12 patients treated with hydroxyurea, 33 adverse events were reported versus 19 reported for 12 patients who did not receive hydroxyurea (p < .05). Our results suggest that that adding hydroxyurea to a regimen of d4T plus ddI and NVP increases toxicity without improving the antiviral effect.

Role of Hydroxyurea in Treatment of Disease Due to Human Immunodeficiency Virus Infection

The potential role of hydroxyurea in the treatment of human immunodeficiency virus (HIV) infection was first supported by in vitro experiments that demonstrated control of viral production in activated and resting T cells. More recently, controlled clinical trials demonstrated that the addition of hydroxyurea to nucleoside-including regimens (chiefly of didanosine but also of stavudine and lamivudine) enhances their antiviral potency. It is believed that the cytostatic effect of hydroxyurea is at least partially responsible for its antiviral effect, through the down-modulation of cellular proliferation. Such an effect has also been credited for the blunted CD4 T cell responses that are characteristically observed when hydroxyurea is added to nucleoside-including regimens. The adjunctive antiviral effect of hydroxyurea-as well as its favorable dosing schedule, safety profile, and cost-makes it a very attractive addition to our therapeutic armamentarium. Further research is urgently needed to delineate the most appropriate use of this compound in the setting of HIV antiretroviral therapy.

Lack of viral selection in human immunodeficiency virus type 1 mother-to-child transmission with primary infection during late pregnancy and/or breastfeeding

Mother-to-child transmission (MTCT) of human immunodeficiency virus type 1 (HIV-1) as described for women with an established infection is, in most cases, associated with the transmission of few maternal variants. This study analysed virus variability in four cases of maternal primary infection occurring during pregnancy and/or breastfeeding. Estimated time of seroconversion was at 4 months of pregnancy for one woman (early seroconversion) and during the last months of pregnancy and/or breastfeeding for the remaining three (late seroconversion). The C2V3 envelope region was analysed in samples of mother-child pairs by molecular cloning and sequencing. Comparisons of nucleotide and amino acid sequences as well as phylogenetic analysis were performed. The results showed low variability in the virus population of both mother and child. Maximum-likelihood analysis showed that, in the early pregnancy seroconversion case, a minor viral variant with further evolution in the child was transmitted, which could indicate a selection event in MTCT or a stochastic event, whereas in the late seroconversion cases, the mothers and childs sequences were intermingled, which is compatible with the transmission of multiple viral variants from the mothers major population. These results could be explained by the less pronounced selective pressure exerted by the immune system in the early stages of the mothers infection, which could play a role in MTCT of HIV-1.

Stavudine plus Lamivudine in Advanced Human Immunodeficiency Virus Disease: A Short-Term Pilot Study

The short-term effects of stavudine (d4T) plus lamivudine (3TC) were evaluated among 48 human immunodeficiency virus-infected patients for whom zidovudine therapy had failed or who could not tolerate zidovudine. Patients were followed for 8 weeks after initiation of open-label d4T plus 3TC. Four patients discontinued therapy, because of neutropenia (1), hepatitis (1), or neuropathy (2). Reduction in virus load was -0.86 (+0.3 to -3.4) log10 copies/mL and CD4 cell increase was 30 (-100 to +290) cells/mm3. Virologic response was associated with a higher CD4 cell count, no prior exposure to d4T and 3TC, and no previous AIDS-defining illness. Virus load reduction for patients naive to 3TC and d4T was -1.47 (-0.14 to -3.37) log10 copies/mL. Short-term use of d4T plus 3TC is safe, well-tolerated, and associated with virologic and substantial immunologic benefits. Further evaluation of d4T and 3TC in combination is warranted.

Antiviral activity and tolerability of amdoxovir with zidovudine in a randomized double-blind placebo-controlled study in HIV-1-infected individuals.

BACKGROUND Amdoxovir acts synergistically with zidovudine in vitro and the combination prevents or delays the selection of thymidine analogue and K65R mutations. In silico studies have shown that a reduced dose of zidovudine (200 mg) results in decreased zidovudine-monophosphate levels, associated with toxicity, while maintaining zidovudine-triphosphate levels, which are associated with antiviral effects. Here, we aimed to assess the short-term tolerability and antiviral activity of amdoxovir in combination with reduced and standard doses of zidovudine. METHODS The study was a double-blind, placebo-controlled study in HIV-1-infected patients not receiving antiretroviral therapy and with plasma HIV-1 RNA > or =5,000 copies/ml. Patients were randomized to 10 days of twice-daily treatment with 200 mg zidovudine, 300 mg zidovudine, 500 mg amdoxovir, 500 mg amdoxovir plus 200 mg zidovudine or 500 mg amdoxovir plus 300 mg zidovudine. The mean change in viral load (VL) log(10) and area under the virus depletion curve (AUC(VL)) from baseline to day 10 were determined. Laboratory and clinical safety monitoring were performed. RESULTS Twenty-four patients were enrolled. The mean VL log(10) change was 0.10 with placebo, -0.69 with zidovudine 200 mg, -0.55 with zidovudine 300 mg, -1.09 with amdoxovir, -2.00 with amdoxovir plus zidovudine (200 mg) and -1.69 with amdoxovir plus zidovudine (300 mg). Amdoxovir plus zidovudine (200 mg) was significantly more potent than amdoxovir monotherapy in AUC(VL) and mean VL decline (P=0.019 and P=0.021, respectively), suggesting synergy. There was markedly decreased VL variability with the combination compared with amdoxovir alone. All adverse events were mild to moderate. CONCLUSION The combination of amdoxovir plus zidovudine appeared synergistic with reduced VL variability. This combined therapy, including the use of a lower zidovudine dosage, warrants further development for the therapy of HIV infection.

Determinants of Treatment Access in a Population-based Cohort of HIV-positive Men and Women Living in Argentina

ObjectiveTo report emerging data on the use of highly active antiretroviral therapy (HAART) in Argentina by assessing patterns of HAART access and late vs early treatment initiation in a population-based cohort of adults infected with HIV type-1.DesignThe Prospective Study on the Use and Monitoring of Antiretroviral Therapy (PUMA) is a study of 883 HIV-positive individuals enrolled in the Argentinean drug treatment program. Individuals were 16 years of age and older and were recruited from 10 clinics across Argentina.MethodsSociodemographic and clinical characteristics were examined using contingency tables (Pearson chi-square test and Fisher exact test) for categoric variables and Wilcoxon rank-sum test for continuous variables. To analyze time to initiation of HAART we used Kaplan-Meier methods and Cox regression.ResultsPatients who initiated HAART were more likely to be older, have an AIDS-defining illness, be an injection drug user (IDU), have a lower median CD4 cell count, have a higher median viral load, and be less likely to be men who have sex with men (MSM). In multivariate analysis, AIDS-defining illness and plasma viral load were significantly associated with time to starting therapy. Patients who received late access were more likely to be diagnosed with AIDS and have higher median plasma viral loads than those receiving early access.ConclusionOur results indicate that despite free availability of treatment, monitoring, and care in Argentina, a significant proportion of men and women are accessing HAART late in the course of HIV disease. Further characterization of the HIV-positive population will allow for a more comprehensive evaluation of the impact of HAART within the Argentinean drug treatment program.