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PubMed2001

The effects of deleterious mutations in cyclically parthenogenetic organisms.

Cyclically parthenogenetic organisms experience benefits of both sexual and asexual reproductive modes in a constant environment. Sexual reproduction generates new genotypes and may facilitate the purging of deleterious mutations whereas asexuality has a two-fold advantage and enables maintenance of well-fitted genotypes. Asexual reproduction can have a drawback as increased linkage may lead to the accumulation of deleterious mutations. This study presents the results of Monte Carlo simulations of small and infinite diploid populations, with deleterious mutations occurring at multiple loci. The recombination rate and the length of the asexual period, interrupted by sexual reproduction, are allowed to vary. Here I show that the fitness of cyclical parthenogenetic population is dependent on the length of the asexual period. Increased length of the asexual period can lead both to increased segregational load following sexual reproduction and to a stronger effect of deleterious mutations on variation at a linked neutral marker, either by reducing or increasing the variation.

Animals↗
PubMed2000

[Conditions of "thymidine analog mutations" (TAMs) in naive patients treated with different combinations of d4T].

Recently, d4T/ddI combination has been associated with the selection of thymidine analogue mutations (TAMs) in 50% of patients with a detectable viral load after 6 to 12 months of this bi-therapy (ALBI, STADI and BMS A1460 tests). We evaluated the rate of selection of the TAMs in naive patients with a viral load of > 200 copies/mL after: 6 months to 1 year of d4T/3TC bi-therapy (group 1); 1 year or more of a treatment including d4T/3TC (group 2); and more than 6 months of tri-therapy including d4T/ddI (group 3). The reverse transcriptase gene has ben studied in 33 patients in group 1, 17 patients in group 2 and ten patients in group 3. For the latter patients, the tri-therapies were as follows: d4T/ddI/PI (n = 5), d4T/ddI/NNRTI (n = 4), d4T/ddI/NRTI (n = 1). For the group 1 patients, at baseline, two patients already had TAMs. At M6, all the patients acquired the 3TC-associated mutations, M184V. Only one patient selected a MDR mutation profile (F116Y, Q151M). At M12, 26 of 33 plasmas were analysed. Only one patient selected one TAM (T215Y). For the group 2 patients, only three patients selected TAMs after more than 30 months of treatment. For the group 3 patients, at baseline, only one patient already harbored TAMs. None of the other patients had selected TAMs. In patients who received d4T/ddI/3TC, only the M184V, the 3TC-associated mutation, was selected. In conclusion, stavudine in association with 3TC selected a low rate of TAMs; in patients receiving a treatment including d4T/3TC, time of exposure to stavudine seemed to be an important parameter for the selection of TAMs; and in contrast to results obtained on d4T/ddI, tri-therapies including d4T/ddI did not select any TAMs, whatever the combination (NRTI, NNRTI, PI).

Anti-HIV Agents↗
PubMed2006

Immunovirologic consequences and safety of short, non-structured interruptions of successful antiretroviral treatment.

OBJECTIVES: The aim was to evaluate the safety of short antiretroviral treatment interruptions and their virologic and immunologic consequences in HIV-infected adults on highly active antiretroviral treatment (HAART) with suppressed viral replication. The viral efficacy upon reintroduction was also evaluated. PATIENTS AND METHODS: All patients with undetectable viral load while on HAART were prospectively followed to detect any treatment interruption. We analysed viral and cellular kinetics, incidence of resistance mutations, clinical outcome and results after therapy resumption. RESULTS: Twenty patients were included, mean time since HIV diagnosis was 95 months and time with undetectable viral load 16 months. Treatment was interrupted because of adverse effects, cancer, tuberculosis or patient will. Treatment was reintroduced after 4 weeks using, if possible, the same combination. HIV viral load was detectable on day 28 after interruption in 18 patients (90%). Median of CD4 cell count (p25-p75) decreased from 478/mm3 (96-716) to 257/mm3 (118-663) (p=0.5). Resistance mutations were found in 9 patients (45%) after interruptions. Treatment was reintroduced in 14 patients; all of them achieved viral suppression. CONCLUSIONS: In patients receiving HAART who have undetectable viral load, an interruption, no longer than 4 weeks, due to any intercurrent problem seems to be safe. Response to resumption can usually be achieved. Due to the frequent development of resistance, a genotypic test during interruption might be helpful.

Adult↗
PubMed2005

Risk of selecting de novo drug-resistance mutations during structured treatment interruptions in patients with chronic HIV infection.

BACKGROUND: Structured treatment interruption (STI) may allow viral replication in the presence of decreased plasma drug levels, with risk of selection of resistance mutations. METHODS: For patients recruited for an STI study, genotypic resistance testing was performed at baseline (before receipt of any treatment), immediately before the STI, and 2 weeks after each interuption of therapy. RESULTS: During 20 (18%) of 112 STI cycles (95% CI, 11%-26%), resistance mutations were selected; 6% of the mutations were de novo (i.e., not detected before the start of STI), and 12% were archived mutations (i.e., mutations already detected before the STI). Overall, resistance mutations during STI were selected in 9 (26%) of 35 patients; 5 (14%) of the mutations were de novo, and 4 (12%) were archived mutations. Mutations conferring resistance to nonnucleoside reverse-transcriptase inhibitors (NNRTIs) were selected in 3 (23%) of 13 patients receiving NNRTI-based regimens (all mutations were de novo). Mutations conferring resistance to lamivudine were selected in 9 (50%) of 18 patients receiving lamivudine-containing regimens (4 [22%] were de novo, and 5 [28%] were archived mutations). Mutations conferring resistance to nucleoside reverse-transcriptase inhibitors (NRTIs), excluding the M184V mutation, were selected in 2 (6%) of 35 recipients of NRTIs (1 [3%] of these mutations was de novo, and 1 [3%] was an archived mutation. Finally, mutations conferring resistance to protease inhibitors were selected in none of the 22 patients receiving protease inhibitors. In most cases, de novo and archived mutations were selected during the first STI cycle, and their number did not increase during successive cycles. Plasma viral load decreased to undetectable levels in all the patients when the earlier drug regimen was reintroduced. CONCLUSIONS: Genotypic mutations are selected during STI in a high proportion of patients (especially in patients receiving NNRTIs or lamivudine). Approximately one-half of selected mutations were archived mutations. Patients who had archived mutations did not have a higher risk of accumulating new mutations than did patients who were infected with wild-type virus before the STI.

Adult↗
PubMed1997

Clinical data sets of human immunodeficiency virus type 1 reverse transcriptase-resistant mutants explained by a mathematical model.

Treatment of human immunodeficiency virus type 1 (HIV-1) infection during the clinical latency phase with drugs inhibiting reverse transcriptase (RT) reduces the HIV-1 RNA load and increases the CD4+ T-cell count. Typically, however, the virus evolves mutations in the RT gene that circumvent the drugs. We develop a mathematical model for this situation. The model distinguishes quiescent from activated CD4+ T cells, incorporates the fact that only activated cells can become productively infected by HIV-1, embodies empirical estimates for the drug resistance and the mutation frequency for each of the HIV-1 drug-resistant mutants, and assumes the antiviral immune response to remain constant over the course of the experiments. We analyze clinical data on the evolution of drug-resistant mutants for the RT inhibitors lamivudine and zidovudine. The results show that the evolutionary sequence of the drug-resistant mutants in both data sets is accounted for by our model, given that lamivudine is more effective than zidovudine. Thus, current empirical estimates of the mutation frequencies and the drug resistances of the mutants suffice for explaining the data. We derive a critical treatment level below which the wild-type HIV-1 RNA load can rebound before the first drug-resistant mutant appears. Our zidovudine data confirm this to be the case. Thus, we demonstrate in the model and the data that the rebound of the HIV-1 RNA load in the case of zidovudine is due to the outgrowth of wild-type virus and the first drug-resistant mutant, whereas that in the case of lamivudine can only be due to the drug-resistant mutants. The evolution of drug resistance proceeds slower in the case of zidovudine because (i) zidovudine is not as effective as lamivudine and (ii) the first zidovudine drug-resistant mutant is competing with the rebounding wild-type virus.

Drug Resistance, Microbial↗
PubMed1996

Molecular and biochemical approaches in the identification of heterozygotes for homocystinuria.

We compared biochemical and molecular methods for the identification of heterozygous carriers of mutations in the cystathionine beta-synthase (CBS) gene. Eleven relatives of seven unrelated patients with homocystinuria due to homozygous CBS deficiency and controls were studied with respect to total homocysteine concentrations before and after methionine loading. In addition, we determined CBS activity in cultured skin fibroblasts and tested for the presence of five known mutations by a PCR-based method in these seven patients, their relatives and controls. The results demonstrate that measurement of homocysteine after methionine loading and assay of CBS enzyme activity in cultured fibroblasts identify most but not all heterozygotes. There was significant correlation between homocysteine concentrations and CBS activities only after methionine loading (r = 0.12, 0.48, 0.48 and 0.50 at 0, 4, 6 and 8 h, respectively). Among the homozygous patients, molecular approaches identified five T833C and two G919A mutations out of 14 independent alleles, confirming the studies of others that these represent the two most prevalent mutations. In addition, we found that three of six heterozygotes with the T833 C allele had post-methionine loading homocysteine levels which overlapped with controls and of the other three, one (as well as an obligate heterozygote who did not carry any of the five mutant alleles tested) had CBS activity comparable to that of controls. These findings demonstrate that genotyping is useful as an adjunctive method for the diagnosis of the heterozygous carrier state of CBS deficiency.

Adolescent↗
PubMed2001

Correlation of hepatitis B virus load with loss of e antigen and emerging drug-resistant variants during lamivudine therapy.

It remains unclear whether sequential assessment of hepatitis B virus (HBV) load during lamivudine therapy can predict the loss of hepatitis B e antigen or emergence of drug-resistant variants. Therefore, a longitudinal study was carried out in 28 consecutive patients with chronic hepatitis B who started lamivudine therapy for a median of 12 months (range, 6-31). HBV DNA copy numbers were determined at 3-month intervals. From month 6 onward, HBV viral load below the detection limit of the PCR was predictive of the loss of envelope antigen (P = 0.043). Continuously detectable HBV DNA during the first 12 months of treatment indicated emergence of drug-resistant variants (P = 0.034). These data suggest that the goal of lamivudine therapy should be complete suppression of serum HBV DNA.

Administration, Oral↗
PubMed2001

ATP-binding cassette transporter A1 (ABCA1) functions as a cholesterol efflux regulatory protein.

ABCA1, an ATP-binding cassette transporter mutated in Tangier disease, promotes cellular phospholipid and cholesterol efflux by loading free apoA-I with these lipids. This process involves binding of apoA-I to the cell surface and phospholipid translocation by ABCA1. The goals of this study were to examine the relationship between ABCA1-mediated lipid efflux and apolipoprotein binding and to determine whether phospholipid and cholesterol efflux are coupled. Inhibition of lipid efflux by glybenclamide treatment or by mutation of the ATP-binding cassette of ABCA1 showed a close correlation between lipid efflux, the binding of apoA-I to cells, and cross-linking of apoA-I to ABCA1. The data suggest that a functionally important apoA-I binding site exists on ABCA1 and that the binding site could also involve lipids. After using cyclodextrin preincubation to deplete cellular cholesterol, ABCA1-mediated cholesterol efflux was abolished but phospholipid efflux and the binding of apoA-I were unaffected. The conditioned media from cyclodextrin-pretreated, ABCA1-expressing cells readily promoted cholesterol efflux when added to fresh cells not expressing ABCA1, indicating that cholesterol efflux can be dissociated from phospholipid efflux. Further, using a photoactivatable cholesterol analog, we showed that ABCA1 did not bind cholesterol directly, even though several other cholesterol-binding proteins specifically bound the cholesterol analog. The data suggest that the binding of apoA-I to ABCA1 leads to the formation of phospholipid-apoA-I complexes, which subsequently promote cholesterol efflux in an autocrine or paracrine fashion.

ATP Binding Cassette Transporter 1↗
PubMed1998

Ionizing radiation and genetic risks. VIII. The concept of mutation component and its use in risk estimation for multifactorial diseases.

Multifactorial diseases, which include the common congenital abnormalities (incidence: 6%) and chronic diseases with onset predominantly in adults (population prevalence: 65%), contribute substantially to human morbidity and mortality. Their transmission patterns do not conform to Mendelian expectations. The model most frequently used to explain their inheritance and to estimate risks to relatives is a Multifactorial Threshold Model (MTM) of disease liability. The MTM assumes that: (i) the disease is due to the joint action of a large number of genetic and environmental factors, each of which contributing a small amount of liability, (ii) the distribution of liability in the population is Gaussian and (iii) individuals whose liability exceeds a certain threshold value are affected by the disease. For most of these diseases, the number of genes involved or the environmental factors are not fully known. In the context of radiation exposures of the population, the question of the extent to which induced mutations will cause an increase in the frequencies of these diseases has remained unanswered. In this paper, we address this problem by using a modified version of MTM which incorporates mutation and selection as two additional parameters. The model assumes a finite number of gene loci and threshold of liability (hence, the designation, Finite-Locus Threshold Model or FLTM). The FLTM permits one to examine the relationship between broad-sense heritability of disease liability and mutation component (MC), the responsiveness of the disease to a change in mutation rate. Through the use of a computer program (in which mutation rate, selection, threshold, recombination rate and environmental variance are input parameters and MC and heritability of liability are output estimates), we studied the MC-heritability relationship for (i) a permanent increase in mutation rate (e.g., when the population sustains radiation exposure in every generation) and (ii) a one-time increase in mutation rate. Our investigation shows that, for a permanent increase in mutation rate of 15%, MC in the first few generations is of the order of 1-2%. This conclusion holds over a broad range of heritability values above about 30%. At equilibrium, however, MC reaches 100%. For a one-time increase in mutation rate, MC reaches its maximum value (of 1-2%) in the first generation, followed by a decline to zero in subsequent generations. These conclusions hold for so many combinations of parameter values (i.e., threshold, selection coefficient, number of loci, environmental variance, spontaneous mutation rate, increases in mutation rate, levels of 'interaction' between genes and recombination rates) that it can be considered to be relatively robust. We also investigated the biological validity of the FLTM in terms of the minimum number of loci, their mutation rates and selection coefficients needed to explain the incidence of multifactorial diseases using the theory of genetic loads. We argue that for common multifactorial diseases, selection coefficients are small in present-day human populations. Consequently, with mutation rates of the order known for Mendelian genes, the FLTM with a few loci and weak selection provides a good approximation for studying the responsiveness of multifactorial diseases to radiation exposures.

Adult↗
PubMed2003

Predictors of the virological response to a change in the antiretroviral treatment regimen in HIV-1-infected patients enrolled in a randomized trial comparing genotyping, phenotyping and standard of care (Narval trial, ANRS 088).

OBJECTIVE: To identify predictors of the virological response to antiretroviral therapy in patients in whom initial therapy has failed. METHODS: The Narval trial was designed to compare phenotyping, genotyping and standard of care for the choice of antiretroviral therapy in patients in whom a protease inhibitor (PI)-containing regimen had failed. Virological success was defined as viral load below 200 copies/ml at week 12. Baseline variables including demographic, clinical and biological characteristics, HIV reverse transcriptase and protease mutations, the randomization arm, the drugs prescribed, as well as adherence to treatment and plasma concentrations of PIs and non-nucleoside reverse transcriptase inhibitors (NNRTIs) at week 12 were tested in the model. Variables that were significantly associated with virological success in univariate analysis were included in a logistic regression model. RESULTS: Five-hundred-and-forty-one patients were randomized. Virological success at week 12 was obtained in 200 patients. In multivariate analysis, the following factors were significantly associated with virological success: prescription of efavirenz to NNRTI-naive patients (OR=4.37; 95% CI: 2.76-6.90), randomization to the genotyping arm (OR=2.13, 1.20-3.79), prescription of lamivudine (OR=1.69, 1.01-2.83) and prescription of abacavir to abacavir-naive patients (OR=1.66, 1.02-2.72). Factors significantly associated with virological failure were prescription of nelfinavir (OR=0.30, 0.13-0.68), a high baseline viral load (OR=0.37, 0.28-0.50), the presence of at least five PI mutations (OR=0.42, 0.26-0.66), the presence of at least three thymidine analogue mutations (OR=0.61, 0.39-0.97) and at least 30 months of prior PI exposure (OR=0.64, 0.41-0.99). CONCLUSIONS: These results confirm that among heavily pretreated patients, prescription of efavirenz to NNRTI-naive patients is associated with a good virological response, while a high baseline viral load, a large number of PI mutations and nelfinavir prescription at baseline are associated with a poor virological response. Genotyping was found to be beneficial, while this was not the case for phenotyping. This work was presented at the XI International HIV Drug Resistance Workshop, Sevilla, Spain, July 3-6 2002 (Abstract N(o)133); and at the XIV International Conference on AIDS, Barcelona, Spain, July 7-11 2002 (Abstract N(o)ThOrB138).

Adult↗
PubMed2005

Plasma biopterin levels and tetrahydrobiopterin responsiveness.

Tetrahydrobiopterin (BH4) responsive hyperphenylalaninemia (HPA) with a mutant phenylalanine hydroxylase (PAH) gene was found during neonatal screening for PKU. This study determined blood BH4 and phenylalanine in two patients with hyperphenylalaninemia following oral load with BH4 10 mg/kg. Our patients underwent neonatal screening for PKU, had normal biopterin metabolism and their PAH mutations were determined. Peak plasma biopterin levels in Case 1, which were reached at between 2 and 4h after loading, were 612, 297, and 178 nmol/L at age 30 days, 55 days, and 19 months, respectively, and the maximum phenylalanine decreasing rates, which were found at 24h, were 54, 16, and 4%, respectively. In Case 2, peak plasma biopterin levels were 747 and 327 nmol/L at age 20 and 55 days, respectively, and the maximum phenylalanine decreasing rates were 39 and 32%, respectively. In the BH4 loading test, the peaks of BH4 in both patients lowered ( approximately 50%), on the same dose schedule of BH4, as patients got older.

Biopterins↗
PubMed2004

Viral phenotype and fitness.

The fitness is a parameter defining the replicative adaptation of an organism to its environment. Recently, the HIV research field has shown renewed interest in the replicative capacity of human immunodeficiency virus type 1 (HIV-1) due to the potential impact of ex vivo viral fitness on population size, drug resistance, and disease progression. In the absence of antiretroviral therapy, strains containing drug-resistance mutations have a reduced fitness compared to the wild-type (wt) quasispecies within the population. Therefore, selective pressure of drug therapy leads to dramatic shifts in the quasispecies distribution and fitness of those mutants with decreased sensitivity to the respective antiretrovirals. Even if the presence of drug resistance mutations can decrease the viral fitness and explain a sustained CD4+T cell count in presence of high viral load, the current treatment guidelines advocate a switch in antiretroviral treatment regimens following the emergence of primary drug resistant mutations and possibly prior to selection of compensatory changes.

Adaptation, Biological↗
PubMed2003

Heteroplasmic ratio of the A3243G mitochondrial DNA mutation in single pancreatic beta cells.

AIMS/HYPOTHESIS: To examine whether there is a high content of mutated mitochondrial DNA in individual pancreatic beta cells from a patient with the A3243G mitochondrial DNA mutation. METHODS: Tissues were available from a patient with diabetes and the A3243G mutation including pancreatic tissue. We quantified the amount of mutated mitochondrial DNA in tissue homogenates and single pancreatic beta cells using hot last cycle PCR. RESULTS: The percentage ratio of mutated to wild-type mtDNA was high in tissues such as muscle and brain (>60%), but surprisingly low in both pancreatic islets and in individual beta cells from these islets. The islets were smaller in the patient than in control subjects in keeping with a decreased beta-cell mass. CONCLUSIONS/INTERPRETATION: These observations suggest that either the beta cells show increased sensitivity to the effects mtDNA mutations on respiratory chain function, and/or cells with a high mutant load are preferentially removed leading to a progressive decrease in the islet beta-cell mass.

Brain↗
PubMed2005

In vivo analysis of replication and immunogenicity of proviral clones of human T-lymphotropic virus type 1 with selective envelope surface-unit mutations.

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell lymphoma/leukemia (ATL). The HTLV-1 envelope gene exhibits limited variability when examined from infected individuals, but has not been tested using infectious clones of the virus in animal models. In vitro assays indicate that HTLV-1 envelope (Env) Ser75Ile, Asn95Asp, and Asn195Asp surface unit (SU) mutants are able to replicate in and immortalize lymphocytes. Herein, we examined the effects of these Env mutants in rabbits inoculated with HTLV-1 immortalized ACH.75, ACH.95, or ACH.195 cell lines (expressing full-length molecular clones with the SU mutations) or the ACH.1 cell line (expressing wild-type SU). All rabbits became infected, and the fidelity of the mutations was maintained throughout the 8-week study. However, SU point mutations resulted in decreased antibody responses to viral group-associated antigen (Gag) and Env antigens. ACH.195 rabbits had a selective decreased antibody response to SU, and one ACH.195 rabbit had an antibody response to both HTLV-1 and HTLV-2 SUs. Some mutant inoculation groups had altered proviral loads. However, peripheral-blood mononuclear cell (PBMC) proviral loads did not correlate with antibody responses. Our data are the first to demonstrate that mutations in critical determinants of HTLV-1 Env SU altered antibody responses and proviral loads, but do not prevent viral replication in vivo.

Amino Acid Substitution↗
PubMed2025

Distinct roles of the two BRCA2 DNA-binding domains in DNA damage repair and replication fork preservation.

Homologous recombination (HR) removes DNA double-strand breaks (DSBs) and preserves stressed DNA replication forks. Successful HR execution requires the tumor suppressor BRCA2, which harbors distinct DNA-binding domains (DBDs): one that possesses three oligonucleotide/oligosaccharide-binding (OB) folds (OB-DBD) and another residing in the C-terminal recombinase binding domain (CTRB-DBD). Here, we employ multi-faceted approaches to delineate the contributions of these domains toward HR and replication fork maintenance. We show that OB-DBD and CTRB-DBD confer single-strand DNA (ssDNA)- and dsDNA-binding capabilities, respectively, and that BRCA2 variants mutated in either domain are impaired in their ability to load the recombinase RAD51 onto ssDNA pre-occupied by RPA. While the CTRB-DBD mutant is modestly affected by DNA break repair, it exhibits a strong defect in the protection of stressed replication forks. In contrast, the OB-DBD is indispensable for both BRCA2 functions. Our study thus defines the unique contributions of the two BRCA2 DBDs in genome maintenance.

BRCA2 Protein↗
PubMed2004

MIV-310 reduces HIV viral load in patients failing multiple antiretroviral therapy: results from a 4-week phase II study.

BACKGROUND: Drug resistance is an increasing problem in the treatment of HIV infection. MIV-310 (alovudine), a nucleoside reverse transcriptase inhibitor, potently inhibits the replication of highly mutated strains of HIV in vitro. We examined the efficacy of MIV-310 in highly pretreated patients. METHODS: In a phase II pilot study, 15 patients failing a current antiretroviral therapy with at least two thymidine-associated mutations (TAM) were given MIV-310 7.5 mg once daily for 4 weeks, in addition to their ongoing treatment. The primary endpoint was the plasma viral load reduction at week 4. RESULTS: At baseline, the median viral load was 3.93 log10 copies/ml and the median CD4 cell count was 360 cells/mm3. After 4 weeks of MIV-310 administration, the median decrease in viral load was -1.13 log10. Interestingly, the median reduction was only -0.57 log10 in the four patients on stavudine, contrasting with a median reduction of -1.88 log10 in the 11 patients not receiving concomitant stavudine. The viral load fell by a median of -1.60 log10 in patients with two to three TAM (n = 7), and by -1.88 log10 in patients with four or five TAM (n = 8). The viral load rebounded in all patients after MIV-310 cessation. No mutations were found in the reverse transcriptase coding region during MIV-310 treatment. MIV-310 was well tolerated, with no serious adverse events and no treatment withdrawals. CONCLUSION: MIV-310 7.5 mg/day efficiently reduced the HIV viral load in patients failing a multiple-drug regimen. Further studies with different dosages and longer administration times are urgently needed.

Adult↗
PubMed2004

Prevalence of antiretroviral drug resistance in the HIV-1-infected urban indigent population in San Francisco: a representative study.

We determined the prevalence of antiretroviral (ARV) resistance in HIV-1 infected indigent persons in San Francisco, California. Three hundred and twenty-seven subjects (159 (49%) ARV naïve, and 168 (51%) ARV-experienced), were recruited during 1996-97 and 1999-2000. Plasma HIV-1 viral load quantification and genotypic resistance testing were performed. Twice as many subjects received nucleoside reverse transcriptase inhibitors (NRTIs) as non-nucleoside reverse transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs); resistance mutation prevalences were 30%, 14% and 16% respectively. Risk of any resistance mutations was strongly and independently associated with prior ARV exposure (OR = 1.3 per year of exposure, P < 0.0001) and with ARV exposure prior to HAART (OR = 2.5, P = 0.015). Prevalences of primary ARV resistance mutations among both treatment-naive and treatment-experienced subjects in this indigent urban population are low compared to other observational cohorts, are directly related to length and type of prior ARV exposure, and did not increase significantly between recruitment periods.

Adolescent↗