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Background: Transmission of drug-resistant variants is influenced by several factors, including the HIV-1 RNA levels in HIV-1 -infected patients. Our study describes the transmitted drug-resistant virus among 1446 French patients diagnosed at the time of primary infection and included from 1996 to 2006 along with the proportion of chronically infected treated patients in the French Hospital Database on HIV (FHDH). Methods: Genotypic resistance tests were performed at the time of primary infection. The proportion of patients with viral load

Objective: To evaluate the frequency of drug-resistant HIV-1 viral strains from patients presenting with primary infection in 1999-2000 and to survey the molecular epidemiology of these viruses circulating in France. Methods: Resistance mutations were detected by sequencing the reverse transcriptase and the protease genes in plasma samples from 249 individuals. Phylogenetic analysis was performed on the reverse transcriptase genes. Results: Ten per cent of patients [26/249; 95% confidence interval (Cl) 7-15%] presented with virus mutations associated with resistance to at least one antiretroviral drug. The distribution of the resistance mutations was as follows: to nucleoside reverse transcriptase inhibitors in 19 (8%; 95% Cl 5-12%) and to non-nucleoside reverse transcriptase inhibitors in 10 (4%; 95% Cl 2-7%). Primary resistance mutations to protease inhibitors were detected in 14 (6%; 95% Cl 3-9%). Twelve patients (5%; 95% Cl 3-8%) presented with virus harbouring mutations associated with resistance to two or three classes of antiretroviral drugs. The median HIV RNA in plasma at enrolment was lower in patients with one or more drug resistance mutations than in patients with no mutations (5.05 log versus 5.47 log, P= 0.05). Phylogenetic analysis revealed that 19% (14-24%) of patients harboured HIV-1 non-B subtype strains; this proportion remained high when Caucasian patients only were considered (14%). Conclusion: This study, performed within the French network on HIV-1 primary infection survey, revealed no change in the frequency of resistant viral strains over time, but showed an increasing prevalence of non-B subtypes overall and among Caucasian individuals.

The authors studied the effect of zidovudine (ZDV) resistance mutation on virologic response to treatment with ZDV or stavudine (d4T) each in combination with lamivudine and indinavir. Viral genotyping was performed on plasma HIV-1 RNA at study entry and concerned 155 patients previously treated with ZDV, didanosine, or zalcitabine and enrolled in the NOVAVIR (Agence National de Recherche sur le SIDA [ANRS] 073) trial. Three virologic responses were investigated: early response (50 copies/mL at week 24), late response (500 copies/mL at week 80), and virologic failure (two HIV-1 RNA5000 copies/mL). Patients were classified as resistant or susceptible to ZDV according to the ANRS algorithm. Plasma viral RNA from 123 of 155 patients had two or more ZDV resistance mutations. The number of ZDV resistance mutations was positively correlated with the duration of prior antiviral therapy (p.001). At week 24, 74% and 77% of patients with virus classified as resistant were responders in the d4T and ZDV arm, respectively. Similar results were found at week 80. Virologic failure was reached in 7 of 24 patients with virus classified as susceptible and in 26 of 131 patients with resistant virus (p =.29). In the ZDV arm, patients classified as resistant had longer times to virologic failure than those classified as susceptible (p =.003). In conclusion, sustained virologic response despite presence of ZDV resistance mutations implies that these mutations do not preclude an early and durable response to treatment with a potent three-drug regimen in these patients. Patients susceptible to ZDV had lower median mean corpuscular volumes and lower random indinavir levels, suggesting that adherence was the main reason for failure.

A retrospective study was set up to investigate the frequency of zidovudine (ZDV)-resistant HIV-1 in infected newborns after ZDV prophylaxis in the French Perinatal Cohort study. Nucleotide sequence analysis was carried out from 34 infants' isolates and 18 maternal plasma samples. Mutations related to ZDV resistance were found in the HIV-1 reverse transcriptase in 7 of 34 children (20%). Evidence of mother-child transmission of ZDV-resistant HIV-1 was found in 4 cases. Phylogenetic analysis showed that 14 of 34 HIV-1 isolates from the infants belonged to non-B subtypes. The presence of ZDV resistance-encoding mutations in the newborn isolates was associated with a longer total duration of exposure to ZDV. In a context of a wide HIV-1 variability, ZDV resistance can be one of the factors contributing to mother-child transmission.

Objective To describe the spontaneous course, before the introduction of highly active antiretroviral therapy (HAART), of HIV-1 RNA during the AIDS-free period of the disease. To assess the predictive value of changes in HIV-1 RNA levels. Design A total of 330 patients with a known date of infection followed in the SEROCO cohort. Methods HIV-1 RNA levels (threshold, 200 copies/ml) were evaluated from 2243 frozen sera obtained from enrolment until the onset of AIDS or until February 1996. Lowess curves were used to describe the variations of viraemia during follow-up. A Cox regression model was used to assess the predictive value of early and updated CD4 cell count and viral load. Results In addition to a lower early viral load, patients who remained AIDS-free had, on average, a longer period of viral load decrease after infection (36 versus 18 months), followed by a slower viral load increase compared with those who progressed to AIDS. A true plateau-phase after the seroconversion period, lasting approximately 4 years, was identified only in patients who remained AIDS-free for at least 90 months. In multivariate analysis, both early viral load and later changes were significant predictors of progression to AIDS. A decrease in the CD4 cell count to less than 200 cells/μl and the onset of a group B condition remained significant predictors of progression. Conclusion Our study extends to the early post-seroconversion phase the prognostic value of extracellular HIV-1 RNA levels. Moreover, our data suggest that, in most HIV-infected individuals, a progressive loss of control of viral replication arises during the early years of HIV-1 infection.

We report the first case of mother-to-child transmission of human immunodeficiency virus type 1 strains harboring multiple mutations including the Q151M multinucleoside reverse transcriptase inhibitor resistance mutation. Sustained virologic success was obtained in the infant with postnatal antiretroviral therapy optimized according to genotypic drug resistance testing and therapeutic drug monitoring.

Objective: To assess the efficacy of combination therapy that includes ritonavir in HIV-1 infected children. Design: A monocentric retrospective study. Patients and Methods: Twenty two children with a minimum follow-up of 6 months under triple therapy including ritonavir were analysed for treatment efficacy. At entry, all the patients were protease inhibitor naive and all but two had received previous antiretroviral therapy during a median period of 5 years. Their initial median CD4+ lymphocyte count and viral load were 121 × 10 6 /l and 5.08 log 10 copies/ml, respectively. Clinical and biological evaluation included clinical assessment every 6 weeks and determination of CD4 cell count and HIV-RNA concentration every 3 months. Results: Median length of follow-up on triple therapy was 15 months (range: 7-21 months). Neither progression in the CDC classification nor death occurred. No significant change in mean weight SD scores was noted when baseline values were compared with values obtained after 1 year of triple therapy. Median CD4 count increases were of 210 × 10 6 /l, 415 × 10 6 /l, and 472 × 10 6 /l cells at 6, 12, and 18 months, respectively. Among the patients baseline characteristics, neither age nor initial CD4 cells count influenced the magnitude of immunologic improvement. There were median decreases of 1.14, 0.95, and 1.5 log 10 per ml of plasma in the concentration of viral RNA at 6, 12, and 18 months respectively. Seven patients maintained an undetectable viral load when under treatment. The introduction of at least one new reverse transcriptase inhibitor at the initiation of triple therapy correlated significantly with a greater viral suppression. Conclusion: Despite variable viral response, antiretroviral-experienced HIV-infected children demonstrated a substantial CD4 cell increase during a median period of 15 months of ritonavir containing combination therapy.

OBJECTIVES To study the genetic rearrangements of HIV-1 reverse transcriptase (RT) in circulating viruses from patients under combination therapy, and to determine the impact of these changes on the virological response to treatment. METHODS Blood samples were extracted from total RNA and amplified by RT-PCR. The HIV-1 RT and protease genes were sequenced by fluorescent dye terminator cycle sequencing. RESULTS Specific rearrangements in the RT coding region (between amino acids 66 and 71) were documented in nine patients. This region, which corresponds to a loop between the beta3 and beta4 strands of the fingers subdomain of RT, is involved in the interaction between the enzyme and the template primer. In vitro data with recombinant enzymes have shown the importance of this domain in the processive polymerization of HIV-1 RT. The rearrangements (eight deletions/insertions and one deletion with conservation of the reading frame) did not affect the overall secondary structure of the fingers subdomain, as assessed by the Garnier Osguthorpe Robson prediction method. The changes were generally stable over a follow-up of 10-12 months. With the exception of two cases, most of the patients of this study did not respond efficiently to antiretroviral therapy as assessed by measurements of plasma viraemia. Correspondingly, the RT and protease genes sequenced from these patients displayed numerous resistance-associated mutations. CONCLUSION Functional and stable rearrangements in the beta3-beta4 hairpin of HIV-1 RT can be found in circulating viruses from patients under combination therapy. These rearrangements may affect the virological response to antiretroviral therapy by increasing the processivity of RT, an enzymatic parameter that reflects the fidelity of the polymerization process.

Objective : To evaluate the antiretroviral effect of a combination of zidovudine (ZDV) and didanosine (ddl) on plasma, peripheral blood mononuclear cells (PBMC) and lymph nodes after 24 weeks. Methods : Eight patients naive of antiretroviral therapy were followed by monthly blood samples and two surgical lymph-node biopsies taken at baseline and after 24 weeks. CD4+ T cells were counted monthly by flow cytometry. Plasma HIV-1 RNA was measured monthly by polymerase chain reaction (PCR). Infectious cellular viraemia was measured monthly by a culture technique. Proviral DNA titres in PBMC were measured by endpoint dilution PCR at baseline and 24 weeks. Infectious HIV-1 and proviral DNA titres were measured in the lymph-node mononuclear cells (LNMC). The total HIV-1 RNA content of lymph nodes was measured by PCR. In some cases, phenotypic resistance to ZDV was measured, and codon 215 and 74 mutations in PBMC and LNMC were analysed. Results : A mean increase in CD4 cell count of 122 x 10 6 /l, a mean decrease in HIV-1 RNA of 1.47 log 10 in plasma and a mean decrease in HIV-1 DNA titre of 0.63 log 10 were found after 24 weeks of therapy. Nevertheless, there were no statistically significant changes in the mean infectious HIV-1 titre in PBMC and LNMC, in the HIV-1 DNA titre in LNMC or in the total lymph-node HIV-1 RNA burden at week 24. Phenotypic or genotypic markers of drug resistance were rarely found in PBMC at week 24, although they were detected in LNMC from some patients. Conclusion : A discrepancy in the therapeutic effect can be observed between lymphoid organs and blood after 24 weeks of therapy with ZDV and ddl. This difference could be explained by the insufficient antiretroviral potency of this combination facing the significant viral burden present in lymph nodes. Development of drug resistance in this compartment prior to blood can be demonstrated in some cases, although other mechanisms remain to be investigated in future studies to explain this difference.

OBJECTIVE To compare two published methods for determining plasma viraemia in HIV-seropositive patients, with reference to a cellular viraemia assay. PATIENTS, PARTICIPANTS Three patient groups were defined according to CD4 cell count: group I, less than 200 x 10(6)/l (23 patients); group II, 200-500 x 10(6)/l (18 patients); and group III, greater than 500 x 10(6)/l (13 patients). METHODS The two reported methodologies were applied to all fresh samples, simultaneously and on the same day. RESULTS The two techniques did not differ significantly in the detection of plasma viraemia: 82.3% of group I patients and 55% of group II patients were positive, while all group III patients were negative. Cellular viraemia was positive for 96% of the overall population. CONCLUSIONS These results, obtained in a network of seven French laboratories involved in clinical trials, confirm that both plasma viraemia and cellular viraemia are useful virological markers.