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PubMed2003

Variety of interpretation systems for human immunodeficiency virus type 1 genotyping: confirmatory information or additional confusion?

The emergence of drug resistance remains a major problem during antiretroviral treatment of patients infected with human immunodeficiency virus type 1 (HIV-1). As phenotypic drug resistance is laborious and expensive to determine, and because numerous specific mutations are known to be correlated with different resistance patterns, genotyping of the reverse transcriptase and protease genes of HIV is fast becoming an integral part of HIV management in industrialized countries. A number of software-based interpretation systems have been developed for the interpretation of the resulting complex nucleotide sequences. These programs either employ rule-based algorithms or are based on a genotype-phenotype database. This paper reviews recent publications that compare different such systems, trying to identify the degree of discordance between different systems and the reasons underlying such discrepant interpretations. The highest discordance rate was observed for nucleoside reverse transcriptase inhibitors (NRTIs) followed by protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). For the NRTIs, it is the role of nucleoside analogue associated mutations, for the PIs and for the NNRTIs, that of secondary mutations that causes most discrepancies. As the complexity of the mutation pattern is likely to increase further with new drugs becoming available, rule-based genotype interpretation algorithms need to be updated frequently. Whilst not recommending one particular system, the authors believe that the correlation of genotypic with clinical data is probably the best way to develop an optimal algorithm.

Algorithms↗
PubMed2004

Evidence for differences in the sexual transmission efficiency of HIV strains with distinct drug resistance genotypes.

BACKGROUND: The transmission of drug-resistant human immunodeficiency virus type 1 (HIV-1) is a matter of major concern, because it could compromise the response to antiretroviral therapy. MATERIAL AND METHODS: From 1997 through 2003, genotypic drug resistance profiles in 89 patients with recent HIV-1 seroconversion were compared in a case-control study with HIV-1 genotypes obtained from 520 subjects identified at Hospital Carlos III in Madrid, Spain, as "potential transmitters" of drug-resistant virus. This group consisted of HIV-infected patients experiencing virologic failure of antiretroviral therapy. RESULTS: Drug resistance mutations were recognized in 15 (16.8%) of 89 patients with recent HIV-1 seroconversion (the seroconverter group), providing resistance to nucleoside reverse-transcriptase inhibitors (NRTIs) in 14.6%, nonnucleoside reverse-transcriptase inhibitors (NNRTIs) in 3.4%, and protease inhibitors (PIs) in 3.4%. Among individuals who were potential transmitters of HIV-1 (the potential transmitter group), drug resistance mutations were found in 80%, providing resistance to NRTIs in 73.7%, NNRTIs in 36.4%, and PIs in 38.7%. The estimated ratio of individuals with recent HIV-1 seroconversion to potential transmitters for drug-resistance genotypes was 0.23 for resistance to NRTIs, 0.09 for resistance to NNRTIs, and 0.09 for resistance to PIs. For specific resistance mutations, the ratio of individuals with recent HIV-1 seroconversion to potential transmitters was 0.18 for 41L, 0.20 for 215Y/F (including revertants), 0.06 for 184V, 0.04 for 103N, and 0.14 for 181C when considering drug resistance mutations in the reverse transcriptase (RT) gene; the ratio was 0.12 for 46L, 0.06 for 82A/T/S, and 0.08 for 90L, when examining PI resistance mutations. CONCLUSION: Strains of HIV with some drug resistance genotypes (41L, 215Y/F, and 181C in the RT gene and 46L in the protease gene) may be more efficiently transmitted than strains with other drug resistance mutations (184V and 103N in the RT gene and 82A/S/T and 90M in the protease gene).

Amino Acid Sequence↗
PubMedDate not supplied

HIV-1 drug resistance in newly infected individuals.

CONTEXT: There is concern that the widespread use of antiretroviral drugs to treat human immunodeficiency virus 1 (HIV-1) infection may result in the increased transmission of drug-resistant virus. OBJECTIVE: To determine the prevalence of drug resistance-conferring mutations and phenotypic resistance to antiretroviral agents in a cohort of individuals newly infected with HIV-1. DESIGN: Case series with genetic analyses of the HIV-1 plasma-derived pol gene using reverse transcriptase polymerase chain reaction followed by direct sequencing of polymerase chain reaction products. Phenotypic analysis was performed with a recombinant virus assay. SETTING AND PATIENTS: Eighty individuals referred, on average, 1.7 months after infection with HIV-1 to the Aaron Diamond AIDS Research Center between July 1995 and April 1999. Subjects were from large urban areas (65 from New York, NY; 11 from Los Angeles, Calif); 60 (75%) were white, and 75 (93.8%) were homosexual men. MAIN OUTCOME MEASURES: Prevalence of known resistance-conferring genotypes and reduced susceptibility to individual antiviral agents by phenotype. RESULTS: Thirteen individuals (16.3%) had genotypes associated with drug resistance to any antiretroviral agent. Virus with known resistance-conferring mutations to any nucleoside reverse transcriptase inhibitors was found in 10 individuals, to any nonnucleoside reverse transcriptase inhibitors in 6 subjects, and to any protease inhibitors in 2 cases. Multidrug-resistant virus was identified in 3 individuals (3.8%). Extensive polymorphism in the protease gene was identified. Interpretation of genotypes and phenotypes was concordant in 57 (85%) of the 67 cases in which both studies were performed. CONCLUSION: The prevalence of HIV-1 variants with known resistance-conferring genotypes to any antiretroviral agent in this cohort of 80 newly infected individuals is 16.3%. These data support expanded use of resistance testing in the setting of primary HIV-1 infection. Clinical trials should be initiated to establish whether therapy guided by resistance testing, compared with the use of empirical triple combination antiretroviral therapy, provides additional virological and immunological benefit when treating primary HIV-1 infection. Further efforts to expand the study of transmission of drug-resistant HIV-1 variants, particularly in cohorts with different epidemiological profiles, are indicated.

Adult↗
PubMed2004

Effects of escin on indinavir crystallization time in the urine of patients with HIV-I infection: a multicenter, randomized, open-label, controlled, four-period crossover trial.

BACKGROUND: The combination of indinavir, a protease inhibitor, and reverse-transcriptase inhibitors is widely used in the treatment of HIV-1 infection. However, precipitation of indinavir crystals in the renal tubular lumen due to the drug's aqueous insolubility may result in characteristic symptoms of flank pain or classic renal colic. An in vitro study has shown that addition of escin to synthetic urine containing indinavir delayed the crystallization time of indinavir. OBJECTIVE: This study examined the efficacy and tolerability of the addition of escin to highly active antiretroviral therapy containing indinavir to delay the crystallization time of indinavir in urine. METHODS: This was a multicenter, randomized, open-label, controlled, 4-period crossover trial in which each period lasted 4 weeks. HIV-1-infected adults receiving treatment with indinavir plus 2 nucleoside analogue reverse-transcriptase inhibitors in whom plasma viral loads had been undetectable (HIV-1 RNA <200 copies/mL) for at least 6 months were randomly assigned to 1 of 2 groups based on the timing of the initiation of escin. Group I received escin during the second and third treatment periods, and group II received escin during the first and fourth treatment periods. The primary end point was the in vitro crystallization time of indinavir in 24-hour urine specimens, determined at the end of each 4-week period. Tolerability was assessed based on the number of patients with a rebound in plasma viral load and on the numbers of clinically and biologically relevant adverse events (including those requiring discontinuation of treatment). Clinical and laboratory evaluations were performed throughout each 4-week period. RESULTS: Fifty HIV-1-infected patients were enrolled, 47 were randomized to treatment (40 [85.1%] men, 7 [14.9%] women; median [interquartile range] age, 36 [34-45] years), and 30 completed the study. Urine pH and plasma and urine indinavir concentrations were unaffected by the addition of escin to antiretroviral treatment. The mean time to the onset of crystallization was 14.7 minutes with escin (95% Cl, 11.8-17.5) and 9.9 minutes without it (95% Cl, 6.7-13.1). Therefore, the addition of escin increased the mean crystallization time by 5.5 minutes (95% Cl, 1.5-9.5; P = 0.008), representing the overall capacity of study treatment to inhibit indinavir crystallization in the urine. Three of 47 patients had mild gastrointestinal symptoms associated with escin treatment. No episodes of nephrolithiasis were recorded during the study or after the completion of study treatment. CONCLUSION: The results of this prospective clinical trial of the effect of escin on indinavir crystallization time support the possibility that indinavir-associated nephrolithiasis may be prevented by means other than overhydration. Further research is needed in greater numbers of patients over longer follow-up times.

Adult↗
PubMed2001

Human immunodeficiency virus 1 strains resistant to nucleoside inhibitors of reverse transcriptase in isolates from the Czech Republic as monitored by line probe assay and nucleotide sequencing.

The genetic resistance to nucleoside inhibitors of the reverse transcriptase (RT) of human immunodeficiency virus I (HIV-1) isolates in the Czech Republic was examined by a line probe assay (LiPA) and nucleotide sequencing. The results of LiPA analysis of 294 blood specimens obtained from 156 patients revealed a high incidence of mutations in the RT gene related to resistance to various drugs (67.3%) in various combinations. Mutations in RT gene (M41L, K70R and T215Y/F) conferring the resistance to zidovudine (ZDV) were most frequent (62.6%), that (M184V) responsible for the resistance to lamivudine (3TC) was less frequent (33.7%), while those linked to the resistance to dideoxyinosine (ddl) and dideoxyinosine together with dideoxycytidine (ddl/ddC) were rather rare (6.5% and 5.1%, respectively). LiPA gave a high rate of uninterpretable results due to codon hybridization failure, especially in HIV-1 isolates of non-B subtype. Thirty-two specimens were analyzed also by direct sequencing of a part of RT gene. The results obtained by LiPA and the sequencing were highly concordant for codons successfully analyzed by both methods, but the sequencing provided information also about the codons that could not be analyzed by LiPA. A high prevalence of resistant strains in the Czech Republic and their heterogeneity justifies a regular HIV-1 resistance testing. LiPA turned out as a fast, powerful and most reliable tool for such a purpose. However, due to an increasing diversity of HIV-1 strains circulating in the Czech Republic, LiPA cannot replace the nucleotide sequence analysis.

Base Sequence↗
PubMed2005

Prospects for the resistance to HIV protease inhibitors: current drug design approaches and perspectives.

One of the major challenges raised by HIV chemotherapy is the insurgence of viral resistance to drugs. Resistance to antiviral therapy has been observed for each of the different classes of anti-viral drugs: nucleoside reverse-transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. The crucial question for AIDS drug research community is: Should we continue the search of new anti-HIV drugs which can overcome HIV resistance insurgence or should we consider resistance to anti-HIV drugs as a futile challenge? This review, focussed specifically on HIV antiprotease drugs, highlights the different strategies which have been developed to design new anti-protease drugs which could overcome HIV resistance, and also reviews the different classes of compounds (peptidomimetic or non-peptidomimetic) actually under investigation in order to face the problem of HIV resistance to drug.

Drug Design↗
PubMed2002

Switch studies: a review.

Many physicians and patients wish to switch from successful protease inhibitor (PI)-based regimens to alternative regimens, usually composed of a nonnucleoside reverse transcriptase inhibitor (NNRTI) or abacavir plus two nucleoside reverse transcriptase inhibitors (NRTIs). This reflects a desire to avoid or reverse the metabolic changes observed during long-term PI-based antiretroviral therapy; to alleviate PI-associated adverse effects; and to improve adherence by simplifying the regimen. Data from a number of randomized and cohort PI switch studies are reviewed. Overall, the results of these studies are mixed, perhaps because of limitations in study design, patient number and duration of follow-up. In most studies, the frequency of virological failure is reduced by switching to a NNRTI regimen. Switching to an abacavir-based regimen is associated with two-fold higher risk of virological failure if mutations in the reverse transcriptase gene pre-exist. Improvements in metabolic and lipid abnormalities have not been uniform but favourable lipid changes have been reported, particularly after switching to nevirapine. Resolution of lipodystrophy symptoms has not been demonstrated objectively, perhaps because of insufficient follow-up and/or the role of NRTIs in this syndrome.

Drug Therapy, Combination↗
PubMed1997

Prophylaxis against HIV-1 infection in chimpanzees by nevirapine, a nonnucleoside inhibitor of reverse transcriptase.

Chimpanzees were challenged with HIV-1IIIB while receiving a short regimen of nevirapine (Viramune), a nonnucleoside inhibitor of HIV-1 reverse transcriptase. The untreated, control chimpanzee developed an infection characterized by seroconversion, viremia in peripheral blood mononuclear cells (PBMCs), and plasma positive for viral RNA. In contrast, the three nevirapine-treated chimpanzees remained negative for all viral markers with the exception of nested polymerase chain reaction (PCR) analysis of PBMCs for viral DNA. Although PBMCs from the three nevirapine-treated chimpanzees tested intermittently positive for viral DNA, this PCR signal disappeared and remained negative for the final five months of the study. These data indicate that orally administered nevirapine provided protection from HIV-1 infection in the chimpanzee model.

Animals↗
PubMed2001

Strategies for treating HIV-related lipodystrophy.

HIV-related lipodystrophy has emerged as one of the most prevalent problems for patients with HIV, since this infection can now be seen as a chronic disease. Despite its growing importance, crucial issues such as aetiopathogenesis, diagnosis, prevention and therapy remain largely unknown and unexplored. Current evidence suggests that aetiology is multifactorial. HIV infection, antiretroviral therapy and patient-related factors probably all contribute to the development of lipodystrophy. The lack of a formal definition and the nature of wasting syndromes that affect HIV-infected patients can hinder the diagnosis and treatment of lipodystrophy. Body fat changes have a major negative impact on the quality of life of patients. Metabolic abnormalities are also well known cardiovascular risk factors that can increase the morbidity and mortality due to cardiovascular disorders in a relatively young population. As yet, we do not know whether lipodystrophy is preventable or reversible. Several therapeutic approaches have been tested with limited success, however potential complications must be considered. These therapeutic approaches include general health measures (diet, exercise and discontinuation of smoking), switching antiretrovirals (from protease inhibitors to non-nucleoside reverse transcriptase inhibitors or abacavir, or from stavudine to other nucleoside reverse transcriptase inhibitors) and use of drugs with metabolic effects (metformin, thiazolidinediones, recombinant growth hormone and anabolic steroids). A judicious use of available data, and opting for an individualised approach seems the best option for management of this problem at present.

Animals↗
PubMedDate not supplied

Antiretroviral therapy in AIDS patients with tuberculosis.

Tuberculosis associated with HIV infection continues to be an important problem throughout the world. Since the advent of HAART, the medication of HIV-infected patients who have to receive concomitant treatment for tuberculosis has become a difficult task. The two main problems faced by clinicians include the significant pharmacokinetic interactions between rifamycins, a cornerstone in antituberculosis therapy, and protease inhibitors and nonnucleoside reverse transcriptase inhibitors, which are essential components of antiretroviral combination regimens, as well as the best moment to initiate antiretroviral therapy in patients with tuberculosis. The therapy of choice for patients with no previous antiretroviral experience includes an antituberculous regimen with rifampin and an efavirenz-based antiretroviral regimen. No dose adjustments of these drugs seem to be necessary. Nevirapine can be an alternative to efavirenz in this situation. For patients who cannot take efavirenz, either due to resistance or intolerance, rifabutin and a boosted protease inhibitor can be coadministered, with the necessary dose adjustments. No definite recommendations can be given regarding the optimal timing of antiretroviral therapy, but a delay of two months after initiation of antituberculosis therapy would be advisable and seems to be safe in most patients.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Prevalence of genotypic resistance among antiretroviral drug-naive HIV-1-infected patients in Belgium.

OBJECTIVES: To estimate the prevalence and the evolution over time (1995-1998) of genotypic resistance to antiviral drugs in antiretroviral drug-naive HIV-1-infected patients in Belgium. DESIGN: Belgian Aids Reference Laboratories provided retrospective samples and clinical data from antiretroviral drug-naive HIV-1-infected patients who visited the hospital for the first time in 1995 (n=45), 1997 (n=75) and 1998 (n=111). Genotypic resistance to the three available classes of drugs was monitored using the Line Probe Assay (Innogenetics, Gent, Belgium). Additionally, ARMS-151 was performed for scoring multinucleoside resistance. RESULTS: The prevalence of genotypic resistance at baseline to nucleoside analogue reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) were each between 10% and 20% for 1995, 1997 and 1998 without an increasing trend over time. For NRTIs, resistance mutations were mainly related to zidovudine in 1995, whereas in 1997 and 1998 baseline resistance was scored for zidovudine, lamivudine or for both drugs simultaneously. No patients displayed the multi-nucleoside resistance Q151M mutation. Baseline resistance mutations to protease inhibitors (PIs) did not rise significantly: 4.4% in 1995, 8% in 1997 and 9.9% in 1998. When scoring any resistance-related mutation, 26.6% displayed genotypic baseline resistance in 1995, 26.6% in 1997 and 31.5% in 1998. DISCUSSION: The prevalence of genotypic baseline resistance to any drug, as scored with LiPA, in naive HIV-1 patients in Belgium is 29%, with baseline resistance mutations to one or several drugs from all available classes of antiviral drugs. The ability of LiPA to pick up minor variants could be an explanation for the higher overall prevalence we observe, when compared to recent estimates in other countries of 16.3% and 22%, which were based on sequencing methods. According to the European guidelines for resistance testing, resistance testing in Belgium before starting antiviral therapy should be considered.

Acquired Immunodeficiency Syndrome↗
PubMed1999

[Antiretroviral agent nevirapine: its pharmacological action and potential for clinical use].

Nevirapine (NVP) is a potent noncompetitive inhibitor of the reverse transcriptase enzyme, which is necessary for HIV replication. NVP selectively inhibits HIV-1 but not HIV-2 and any of the human DNA polymerases. NVP is active against ZDV-resistant HIV-1 and synergistic with nonnucleoside reverse transcriptase inhibitors. NVP has a favorable pharmacokinetic profile, becomes widely distributed throughout body tissues including the central nervous system, and is active in the adult at an oral dose of 200 mg administered twice daily after a 2 week lead-in dose of 200 mg/day due to its long elimination half life. Although the currently used protease inhibitors (PIs) may undergo more rapid rates of metabolism because NVP induces CYP3A, No dosage adjustments are required when NVP is taken in combination with PIs so far. When administered in triple combinations with antiretroviral agents, the antiviral effect of NVP has been profound and sustained in HIV-infected patients, particularly in naive patients to antiretroviral therapy. Resistance to NVP is rapid when given as monotherapy, but this is altered and made less clinically relevant when NVP is administered as a triple combination. NVP has a safety profile that does not overlap with other antiretroviral therapies, the most common treatment-limiting reaction being rash. It seems that NVP would be a very useful option in combination with antiretroviral agents.

Adult↗
PubMed2006

Are plasma levels valid surrogates for cellular concentrations of antiretroviral drugs in HIV-infected patients?

Total plasma concentrations are currently measured for therapeutic drug monitoring of HIV protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs). However, the pharmacological target of antiretroviral drugs reside inside cells. To study the variability of their cellular accumulation, and to determine to which extent total plasma concentrations (TPC) correlate with cellular concentrations (CC), plasma and peripheral blood mononuclear cells (PBMCs) were simultaneously collected at single random times after drug intake from 133 HIV infected patients. TPC levels were analysed by high-performance liquid chromatography with ultraviolet detection and CC by LC-MS/MS from peripheral blood mononuclear cells. The best correlations between TPC and CC were observed for nelfinavir (NFV, slope=0.93, r=0.85), saquinavir (SQV, slope=0.76, r=0.80) and lopinavir (LPV, slope=0.87, r=0.63). By contrast, TPC of efavirenz (EFV) exhibited a moderate correlation with CC (slope=0.69, r=0.58), while no correlation was found for nevirapine (NVP, slope=-0.3, r=0.1). Interindividual variability in the CC/TPC ratio was lower for protease inhibitors (coefficients of variation 76%, 61%, and 80% for SQV, NFV and LPV, respectively) than for nonnucleoside reverse transcriptase inhibitors (coefficients of variation 101% and 318%, for EFV and NVP). As routine CC measurement raises practical difficulties, well-correlated plasma concentrations (ie, NFV, SQV and LPV) can probably be considered as appropriate surrogates for cellular drug exposure. For drugs such as EFV or NVP, there may be room for therapeutic drug monitoring improvement using either direct CC determination or other predictive factors such as genotyping of transporters or metabolizing enzyme genes.

Adult↗
PubMed2006

New antiretroviral drugs in clinical use.

The advent of combination antiretroviral therapy for the treatment of human immunodeficiency virus (HIV) infection has dramatically changed the prognosis and quality of life of HIV-infected adults and children. To date, there are 21 antiretroviral agents available with only 11 agents being approved for the use in young children less than 6 years of age. The currently available antiretroviral agents belong to four different classes; nucleoside/nucleotide reverse transcriptase inhibitors (NRTI, NtRTI), non-nucleoside reverse transcriptase inhibitors (NNRTI), protease inhibitors (PI), and a new class of fusion inhibitors (FI). It is recommended that the treatment regimen should be a combination of at least 3 drugs from different drug classes as this has been shown to slow disease progression, improve survival, and result in better virologic and immunologic responses. Treatment with antiretroviral agents is frequently complicated by the issues of adherence, tolerability, long term toxicity and drug resistance. Many efforts have been made to develop new antiretroviral agents with greater potency, higher tolerability profiles and better convenience. Some new agents are also effective against drug-resistant strains of HIV. Since 2001, there were 7 new antiretroviral agents and 2 fixed-dose multidrug formulations being approved for the treatment of HIV infection, most are approved only for use in adults. In this article, we will review new antiretroviral agents including emtricitabine, tenofovir disoproxil fumarate, atazanavir, fosamprenavir, tipranavir and enfuvirtide. Pediatric information on these drugs will be provided when available.

Anti-HIV Agents↗
PubMed2001

Current Options for the Therapy of Chronic Hepatitis B Infection.

Until recently the only available treatment for chronic hepatitis B was interferon-alpha. Over the past few years a new class of antiviral has become available, the reverse transcriptase inhibitors. Lamivudine is a nucleoside analogue reverse transcriptase inhibitor that was recently approved in many countries for the treatment of hepatitis B. Despite the potent action of lamivudine, the development of new antivirals and new strategies to treat hepatitis B are still the major goal. We review the latest options for therapy of chronic hepatitis B, including combination strategies that could be an approach to improving the response rate of antivirals.

Journal Article↗
PubMed2005

Lessons learned from use of highly active antiretroviral therapy in Africa.

BACKGROUND: Because antiretrovirals are becoming increasingly available in developing countries, we reviewed the findings of studies that have documented highly active antiretroviral therapy (HAART) use in Africa to identify lessons learned. With the World Health Organization (WHO) guidelines used as a frame of reference, we assessed the feasibility of implementing such programs in Africa. Moreover, clinical and laboratory outcomes were compiled to determine the effectiveness of HAART programs. METHODS: We searched academic databases and recent conference abstracts for studies, and we included all studies that documented patients receiving HAART in Africa. In particular, we examined studies for such program features as type of regimen and frequency of monitoring, in addition to evaluations of patient outcomes. RESULTS: Twenty-eight articles and abstracts involving studies from 14 African countries were reviewed. Overall, 6052 patients (96.4%) were receiving HAART, mainly consisting of 2 nucleoside reverse-transcriptase inhibitors (NRTIs) and 1 nonnucleoside reverse-transcriptase inhibitor. All studies reported an increase in mean and median CD4 cell counts, and a median of 73% of patients achieved undetectable viral loads by the end of the study period. Monitoring of CD4 cell count and viral load at 6-month intervals was completed by all studies. The median weight gained was 5.0 kg, and the median mortality rate was 7.4% (range, 0%-27%). Six studies reported that 68%-99% of patients took >95% of medications. Five studies measured drug resistance; most cases of resistance involved NRTIs. CONCLUSIONS: Many studies reported positive health outcomes, including high levels of treatment adherence that were comparable to those of industrialized countries. Regimens and monitoring means based on WHO guidelines were implemented--and at times, exceeded--in all studies reviewed. We found compelling evidence that HAART can be feasibly administered in resource-limited settings.

Africa↗
PubMed2004

GENOPHAR: a randomized study of plasma drug measurements in association with genotypic resistance testing and expert advice to optimize therapy in patients failing antiretroviral therapy.

OBJECTIVES: To evaluate the benefits of therapeutic drug monitoring (TDM) in association with genotypic resistance testing and expert advice to optimize therapy in multiexperienced patients infected with HIV-1. METHODS: Patients with a viral load>1000 HIV-1 RNA copies/mL and an unchanged antiretroviral therapy regimen over the last 3 months were randomized into two groups: a genotypic group (G) and a geno-pharmacological group (GP). Treatment was selected by an expert committee according to genotypic resistance testing (the G and GP groups) and TDM (the GP group) at week 4. Treatment could be modified at each visit according to toxicity, poor virological response and TDM. Results of TDM were withheld from the G group until week 12. The primary endpoint of the study was the percentage of patients with viral load<200 copies/mL at week 12. RESULTS: A total of 134 patients were randomized in the study, with 67 in each group, and included in the intent-to-treat (ITT) analysis. At baseline, median values were as follows: viral load (log(10) copies/mL): G=4.1, GP=4.0; CD4 cell count (cells/microL): G=292, GP=294; and number of prior drugs: G=7, GP=8. The median number of resistance mutations was five in the G group [nucleoside reverse transcriptase inhibitors (NRTIs)=three; non-nucleoside reverse transcriptase inhibitors (NNRTIs)=one; protease inhibitors (PI)=one] and seven in the GP group (NRTI=four; NNRTI=two; PI=one). At week 8, treatment was adjusted according to the TDM in 13 of the 67 patients in the GP group (19%). By ITT missing equal failure analysis at week 12, and after only one intervention according to plasma concentration results, a viral load<200 copies/mL was achieved in 30 of the 67 patients (45%) in the G group and in 29 of the 67 patients (43%) in the GP group (not significant). In the multivariate analysis, only prior exposure to at least two PIs at baseline gave a poor response to subsequent antiretroviral therapy. At week 24, a viral load<200 copies/mL was achieved in 35 of the 67 patients (52%) in the G group and in 40 of the 67 patients (60%) in the GP group. CONCLUSIONS: A statistically significant benefit of using TDM was not found in this short-term study where patients appeared to be adherent. However, combining genotypic resistance testing with the use of an expert committee to monitor subsequent therapy individually in patients with multiple resistance mutations was associated with high antiviral efficacy.

Adolescent↗
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↗