Archived HIV-1 DNA resistance mutations to rilpivirine and etravirine in successfully treated HIV-1-infected individuals pre-exposed to efavirenz or nevirapine.

OBJECTIVES: Efavirenz and nevirapine failure is associated with a rapid selection of resistance-associated mutations (RAMs), which may impact on etravirine or rilpivirine susceptibility. However, RAMs for rilpivirine and etravirine cannot be reported on previous resistance genotypes because these specific RAMs were not analyzed at that time. Therefore, our objective was to determine, in virologically suppressed HIV-1-infected individuals, the presence of RAMs to rilpivirine, etravirine and the combination of tenofovir/emtricitabine/rilpivirine in HIV-1 DNA from individuals previously exposed to efavirenz and/or nevirapine. METHODS: The studied population included 169 treatment-experienced individuals enrolled in the ANRS 138-EASIER trial who previously failed on and/or were intolerant to efavirenz and/or nevirapine and who had plasma HIV-1 RNA<400 copies/mL. Resistance to rilpivirine, etravirine, tenofovir and emtricitabine by bulk sequencing was performed on extracted HIV-1 DNA from whole blood collected at the time of trial inclusion. RESULTS: Reverse transcriptase gene amplification was successful in 128/169 (76%) individuals and 95% of HIV-1 were infected with subtype B. Rilpivirine RAMs were detected in 41 (32%) individuals, with highest frequency for the mutations Y181C/I/V (18%), K101E/P (7%) and E138A/G/K/Q/R/S (6%) and the association L100I+K103N/S (5%). Etravirine RAMs were detected in five (4%) individuals. Resistance to emtricitabine, tenofovir and at least one drug included in the combination of tenofovir/emtricitabine/rilpivirine were detected in 72 (56%), 12 (9%) and 88 (69%), respectively. CONCLUSIONS: In individuals with suppressed viraemia under antiretroviral therapy (ART), but who had been previously exposed to an efavirenz and/or nevirapine-based regimen, rilpivirine RAMs are frequent and etravirine RAMs are rare. This finding suggests that the switch to a rilpivirine-based regimen should not be recommended.

Comparison of resistance mutation patterns in historical plasma HIV RNA genotypes with those in current proviral HIV DNA genotypes among extensively treated patients with suppressed replication.

OBJECTIVES: Heavily treatment-experienced patients with good virological control could be at risk of virological failure on switching to a new regimen if pre-existing drug resistance is not taken into account. We examined whether genotyping based on cellular HIV-1 DNA during controlled viraemia identifies resistance mutations detected in plasma HIV-1 RNA during treatment with previous antiretroviral regimens. PATIENTS AND METHODS: All 169 patients enrolled in the Agence Nationale de Recherche sur le SIDA (ANRS) 138-intEgrase inhibitor MK_0518 to Avoid Subcutaneous Injections of EnfuviRtide (EASIER) trial had already received three antiretroviral drug classes [nucleoside reverse transcriptase inhibitor (NRTI), nonnucleoside reverse transcriptase inhibitor (NNRTI) and protease inhibitor (PI)] and had plasma HIV-1 RNA<400 copies/ml at baseline. The results of previous resistance genotyping of plasma HIV-1 RNA in individual patients were compared with those of resistance genotyping of whole-blood HIV-1 DNA at randomization. RESULTS: A median of 4 plasma RNA genotypes were available for the 169 patients. The median numbers of resistance mutations in HIV-1 RNA and DNA were, respectively, 5 and 4 for NRTIs, 2 and 1 for NNRTIs, and 10 and 8 for PIs. The difference was significant for all three drug classes (P=0.001). Resistance to at least one antiretroviral drug was detected exclusively in HIV-1 RNA or in DNA in 63% and 13% of patients for NRTI, 47% and 1% of patients for NNRTI, and 50% and 7% of patients for PI, respectively. CONCLUSION: This study shows that, among highly treatment-experienced patients on effective highly active antiretroviral therapy, resistance genotyping of HIV-1 DNA detects fewer resistance mutations than previous analyses of HIV-1 RNA. These results have implications for patient management and for the design of switch studies.

Toxoplasma gondii infection in advanced HIV infection.

OBJECTIVE: To study Toxoplasma encephalitis (TE) in advanced HIV infection, including predictive factors, possible prophylactic regimens and impact on survival. DESIGN: Epidemiological analysis of data collected prospectively during the Alpha study, a double-blind, randomized clinical trial, comparing two doses of dideoxyinosine in patients with advanced HIV disease. PATIENTS: First episode of TE occurred in 75 out of 499 patients participating in the trial. METHODS: Kaplan-Meier estimates and semi-parametric Cox's model were used. RESULTS: A low CD4 cell count and a positive Toxoplasma serology were strongly predictive of the occurrence of TE. In patients with CD4 counts < 100 x 10(6)/l and a positive Toxoplasma serology at entry to the study, the 12-month TE incidence was 25.4%. Patients who were receiving at entry any of the following potentially antitoxoplasmic drugs: trimethoprim-sulphamethoxazole, pyrimethamine, dapsone, pyrimethamine-sulphadoxine or sulphadiazine, had a lower TE incidence than those who were not; 6.2 versus 18.8%, respectively (P < 0.001). The rate of survival 12 months after TE was 29.6%. Even after adjusting the major prognostic covariates, TE was predictive of death (P < 0.001; relative risk, 1.8). CONCLUSIONS: The high HIV incidence, morbidity and mortality in high-prevalence areas suggests that primary prophylaxis should be given in patients at high risk for toxoplasmic reactivation.

First analysis of tumor regression for the European randomized trial of etanidazole combined with radiotherapy in head and neck carcinomas.

From July 1987 to July 1990, 374 patients were randomized in a multicenter trial coordinated by the Gustave-Roussy Institute. Patients were treated either by radiotherapy alone (RT) or by combined etanidazole with radiotherapy (ETA). The same radiotherapy protocol was used in both arms. Major deviations from the protocol occurred in 16% of the patients. Etanidazole was given at a dose of 2 g/m2, 3 times per week, for a total of 30-34 g/m2. Seventeen percent of the patients received less than 14 injections (4% refused, 12% presented a toxicity, 1% died before beginning). The rate of neuropathy was 28% in the ETA arm and 3% in the RT arm. Acute radiotherapy reactions occurred in similar proportions in both arms. The 3-month rates of complete regression are presently 75.3% in the RT alone group and 77.6% in the ETA group; this difference is not significant. No definitive results are presently available and we must wait for the two-year survival results. In addition, if a meta-analysis could be performed with the parallel RTOG study, the results would be more valid.

Progress report of a phase II and a phase III trial with etanidazole (SR-2508): a multicentre European study.

A group of 6 European cancer centers, coordinated by the Institut Gustave-Roussy, began a phase II trial of the radiosensitizing drug, etanidazole, in November 1986. The trial was designed to study the toxicity of the drug and the feasibility of a phase III trial on the combination of etanidazole with radiotherapy for treating head and neck squamous cell carcinomas. Thirty-one patients were included in the phase II trial between November 1986 and June 1987; 25 completed the whole course of treatment. Most of the neuropathies occurred during the two weeks following radiotherapy, but had no major effect on radiotherapy itself. The area under the curve (AUC) was measured in 22 patients; there was no correlation between total AUC and the incidence of neuropathy, although there was a trend towards more neuropathies at high total AUC. The toxicity of Eta did not appear excessive. A phase III trial was therefore begun in July 1987. Twenty-nine centers in 5 European countries (France, Italy, Germany, Austria and the UK) took part. A total of 330 patients had been enrolled by the end of November 1989. This report presents the results available to date. 15% of the patients treated with Eta plus radiotherapy have received less than 15 Eta injections, mainly because of skin rashes (5%), peripheral neuropathies (3%) or patient refusal (3%). The overall frequency of neuropathies was 27%, but most were grade I and occur mainly after treatment. There were similar percentages of radiotherapy-related toxicities, mainly acute reactions in irradiated normal tissues, in both Eta and control arms.(ABSTRACT TRUNCATED AT 250 WORDS)

Oral contraceptive use and risk of benign breast disease in a French case-control study of young women.

We report the results of a French hospital-based case-control study designed to analyse the relation between the use of oral contraceptives (OC) and the risk of benign breast disease (BBD). The cases were 286 women, each less than 46 years old, with BBD histologically verified between 1982 and 1985. Controls were 382 patients, matched to cases on year of birth and month of interview, and who were hospitalized for a non-malignant disease other than BBD. Odds ratios were estimated by multivariate regression, taking into account level of education, place of residence, family history of breast cancer, age at menarche, number of children, age at first full-term pregnancy and Quetelet index. The risk of BBD was found to decrease significantly with a longer use of OC before the first full-term pregnancy (FFTP), but there was no association between the risk of BBD and the duration of OC use after FFTP. OC use before FFTP reduced the risk of non-proliferative disease, but did not significantly affect the risk of proliferative disease. These results did not depend on the amount of oestrogen (0.05 mg or more vs < 0.05 mg) contained in OC.

PIP: This article reports the findings of a French-based case-control study examining the relationship between risk of benign breast disease (BBD) and oral contraceptive (OC) use. Special emphasis was given to duration of OC use before and after the first full-term pregnancy (FFTP). Conditional multivariate logistic regression was the statistical process used to analyze the findings. 286 women with verified BBD were studied. 382 women, who were hospitalized for a non-BBD disease, were used as controls. Each case was matched with at least one control. 7 confounders were adjusted for. Confounders included family history of breast cancer, level of education, place of residence, age at menarche, number of children, age at FFTP, and Quetelet index. The risk of BBD decreased with longer OC use before the FFTP. There was no association observed between risk of developing BBD and the duration of OC use after the FFTP. OC use before the FFTP reduced the risk of non-proliferative disease, but did not significantly affect the risk of proliferative disease.

[Oral contraception and benign breast diseases: point of view of the epidemiologist]. / Contraception orale et mastopathies bénignes: le point de vue de l'épidémiologiste.

The study of the association between oral contraceptives (OC) and benign breast disease (BBD) is of great interest for the epidemiologist, because of the impact that this association may have on the risk of breast cancer. In fact, three factors have to be analysed simultaneously: OC use, the occurrence of BBD and the occurrence of breast cancer. This analysis is complex because two out of the three factors are not univocal in their definition (various composition and doses for pills, numerous histologic types of BBD). Moreover, a fourth parameter is to take into account: the time factor. This last factor intervenes in the chronological order of events (OC before or after BBD), and for the use of different types of pills (duration of use, age at the start of OC use before or after the first full-term pregnancy, etc). Although all the relationships between these different factors are still insufficiently known at the present time, certain points are acquired: 1) OC use decreases the risk of BBD (particularly when pills contain high doses of progestogens); 2) a history of BBD increases the risk of breast cancer (particularly when BBD is a fibrocystic mastosis with cellular atypia); 3) in spite of the decrease in the risk of BBD associated with OC use, OC use does not decrease the risk of breast cancer. For a long time, this third proposition appeared as paradoxal. In 1986, Stadel and Schlesselman tried to estimate the terms of this paradoxe. Their estimations allowed to show that the risk of breast cancer associated with OC use, for women with a history of BBD, was overestimated in all previous reports. Indeed, the decrease of the occurrence of BBD due to OC use, which was associated with an important reduction in the number of breast cancer cases, was not taken into account in the estimation of this risk. Other epidemiological investigations with a greater number of subjects are needed to further analyse complex relationships between OC use, BBD and breast cancer.

Risk factors for esophageal candidiasis in a large cohort of HIV-infected patients treated with nucleoside analogues.

To assess the risk factors for esophageal candidiasis (EC), a cohort study and a case-control study were conducted using 1,368 French patients who were already participating in the Delta trial (which compared different types of antiretroviral therapy in HIV-infected patients) and who had no previous history of EC. During a median follow-up period of 19 months, 87 (6%) patients developed EC. The results of the cohort study showed an increased risk of EC associated with a low baseline CD4+ cell count (P<0.0001), a high baseline plasma HIV RNA level (P < 0.0001) and prior zidovudine therapy (P = 0.02) at entry to the study. The case-control study revealed an increased risk of EC in patients with a recent low CD4+ cell count (P < 0.0002), recent antibacterial chemotherapy (P = 0.01) and oral candidiasis (P < 0.05). Cotrimoxazole prophylaxis also increased the risk of EC (P = 0.04) in the case-control study.

Adverse reactions to cotrimoxazole in HIV-infected patients: predictive factors and subsequent HIV disease progression.

The relationship between the onset of adverse events to cotrimoxazole in HIV-infected patients and the subsequent development of toxoplasmosis, other AIDS-defining events and survival was studied in 592 French patients who first received cotrimoxazole during the Delta trial. Low CD4+ cell count at cotrimoxazole introduction was the only factor associated with the onset of adverse reactions. The occurrence of toxoplasmosis and first AIDS-defining events were significantly and independently linked to a low CD4+ cell count at cotrimoxazole introduction (p < 0.0001) and to previous cotrimoxazole withdrawal for adverse events (p = 0.004 and p < 0.0001, respectively), but not to previous cotrimoxazole withdrawal for reasons other than adverse events, as compared to patients who did not discontinue taking cotrimoxazole during this survey. The survival rate was significantly shorter among both patients who stopped taking cotrimoxazole for adverse events and for other reasons (p = 0.03 and p = 0.0001, respectively), as compared to patients who continued to take cotrimoxazole.

Intention-to-treat vs. on-treatment analyses of clinical trial data: experience from a study of pyrimethamine in the primary prophylaxis of toxoplasmosis in HIV-infected patients. ANRS 005/ACTG 154 Trial Group.

Randomized clinical trials analyzed by the intent-to-treat approach provide unbiased comparisons among treatment groups. To avoid dilution of treatment effect, many people also perform an analysis by treatment actually received, although this method may introduce bias into the results. This paper presents several approaches used for analyzing data of a recent trial and the difficulties encountered in interpreting the results of each approach. The ANRS 005/ACTG 154 Study was a double-blind, placebo-controlled, randomized, international (French, U.S., and Spanish) multicenter trial designed to assess the effectiveness of pyrimethamine for the primary prophylaxis of cerebral toxoplasmosis (CT) in HIV-infected patients with advanced immunodeficiency. In the intention-to-treat analysis, the cumulative probability of CT at 1 year did not differ significantly between the pyrimethamine arm (11.9%) and the placebo arm (13.1%), Hazard Ratio (HR) = 0.94 (95% Confidence Interval (CI) = 0.62-1.42), whereas an on-treatment analysis resulted in a significant difference: 4.2% in the pyrimethamine arm and 12.4% in the placebo arm, HR = 0.44 (95% CI = 0.24-0.80). The data showed a significant interaction between compliance and treatment outcome; and side effects were more frequently cited as reasons for compliance violations in the pyrimethamine group. Several different analytic approaches (censoring data at the time patients discontinued the study medication only for selected reasons) failed to explain the disparity between the estimation of effect of pyrimethamine by the intention-to-treat and on-treatment analyses. This experience led us to believe that comparing the results of both analyses was the best method to convince clinicians that intention-to-treat was the only interpretable analysis. We were concerned that even if pyrimethamine had a beneficial effect, it was very difficult (1) to quantify and (2) to apply to clinical practice unless one could predict the occurrence of study drug discontinuation for each patient at the time of treatment assignment. Although exploratory analyses may yield clinically relevant information and useful clarifications in the evaluation of treatments, intention-to-treat remains the only interpretable analysis of clinical trials.