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PubMed1999

Antiretrovirals.

Deaths related to the human immunodeficiency virus (HIV) and the acquired immunodeficiency syndrome and the incidence of opportunistic infections have been drastically decreased in the industrialized world. These reductions are mainly due to recent advances in the management of HIV infection, including the availability of new therapies. Until November 1995, the antiretroviral drugs available and approved by the Food and Drug Administration for clinical use in the United States consisted of only four nucleoside analogue reverse transcriptase inhibitors: zidovudine, zalcitabine, didanosine, and stavudine. Since then, 2 new classes of agents and 10 new agents have been approved; thus, the number of available antiretroviral drugs has more than tripled. Additional drugs and newer classes of antiretrovirals are in various stages of development. Because of the availability of more drugs, the complexity of HIV treatment has increased. Selecting an appropriate antiretroviral therapeutic regimen involves addressing multiple interdependent issues, including patient adherence, pharmacokinetic properties of the drugs (including food effects and drug-drug interactions), drug resistance, and overlapping adverse effects.

Adolescent↗
PubMed2004

Correlation between rules-based interpretation and virtual phenotype interpretation of HIV-1 genotypes for predicting drug resistance in HIV-infected individuals.

Drug resistance testing provides useful information for managing HIV-infected patients. Phenotyping could add complementary information to genotyping and occasionally be more useful, although is less available to clinicians. Large paired geno-pheno databases have allowed the prediction of phenotypes from genotypes. However, the accuracy of these virtual phenotypes (vPT) in a clinical setting has not been well assessed yet. We analyzed the concordance between vPT and interpreted genotype (GT) in 105 samples belonging to treatment-experienced HIV-infected patients. A high concordance was seen when examining both non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI) (r = 0.95 either), while it was lower for nucleoside analogs (r = 0.79). The drugs with lower concordance were abacavir (71.1%), tenofovir (71.5%) and didanosine (71.9%). In 20% of specimens (21/105), the vPT did not provide results for all approved drugs. These were mainly samples with a high number of drug resistance mutations or rare genotypes, which seem to be underepresented in the VircoNET database. Overall, there is good correlation between vPT/GT, especially for PI and NNRTI. The inclusion of additional sequences in the VircoNET database, mainly those derived from heavily treatment-experienced patients and/or from patients failing the most recently approved drugs might improve its performance.

Adenine↗
PubMed2004

High resistance to antiretroviral drugs: the Indian experience.

Effective antiretroviral treatment (ART) has significantly reduced the morbidity and mortality among people living with HIV/AIDS. The emergence of drug resistance is the major obstacle to the successful implementation of long-term treatment strategy of HIV disease. Hence, monitoring the resistance to ART is an essential task. The MGM Medical College in Navi Mumbai is the only national facility with the capacity to monitor ART resistance using tissue culture technique. The main objective of the study was to determine the prevalence of primary and secondary resistance between May 1997 and April 2003. Four hundred and sixty viral isolates of 74 individuals were tested for ART resistance using tissue culture-based protocol (McGill University, Canada). These included 287 primary and 173 follow-up viral isolates. Following activation of tissue culture, a panel of 12 antiretroviral drugs in concentrations from 0.038 mg/mL to 0.090 mg/mL was tested. The resistance was determined on the basis of the production of p24 antigen at the end of 72 and 144 hours of incubation. The overall resistance against reverse transcriptase inhibitors (RTIs) was 33.7% and that to protease inhibitors (PIs) was 21.5%. However, prevalence of primary resistance among ART näive to RTIs was 14/208 (6.7%) of isolates and that to (PIs) was 2/79(2.5%) of isolates. The incidence of resistance to RTI was 22/500 years (4.4/100 years) and that to PIs was 8/253.6 years (3.2/100 years). It is possible that non-B subtypes of HIV-1 that are prevalent in most developing countries are likely to develop resistance rapidly after ART. However, common factors that influence development of resistance such as poor adherence, inadequate 'wild' doses and regimens, and poor monitoring were not validated in the study. Unless active surveillance is instituted, these factors can pose major challenge for the management of people on ART in developing countries.

Antiretroviral Therapy, Highly Active↗
PubMed2003

Characteristics of HIV antiretroviral treatments, access and adherence in an ethnically diverse sample of men who have sex with men.

Data regarding HIV antiretroviral treatment regimens, access to treatment and medical care, and adherence to medications were collected as part of the Seropositive Urban Men's Study, a formative study of HIV-positive men who have sex with men. Participants (N = 456) were recruited from AIDS service organizations, mainstream gay venues and public/commercial sex environments. The sample was 94% gay or bisexually-identified; 29% were African American, 24% Latino and 30% white. The majority (71%) indicated being on antiretroviral treatment, and most were taking a protease inhibitor/nucleoside reverse transcriptase inhibitor combination. African American men in New York City were less likely to be on treatment. Among those on treatment (n = 322), 51% reported at least one day in which they had missed a dose of their medication and the mean number of days in which a dose was missed (in the past 30 days) was 1.72. Multivariate analyses indicated that avoidant coping, frequency of drinking alcohol and difficulty in communicating with sex partners about HIV were related to days of missed doses, suggesting the need or desire to escape from the reality of life with HIV as a potential explanation for poor adherence.

Adult↗
PubMed2000

Antiretroviral pharmacology in pregnant women and their newborns.

The physiologic changes of pregnancy have an impact on antiretroviral pharmacokinetic parameters, but the effect is generally not of sufficient magnitude to warrant alterations in dosing. Although administration of oral zidovudine during labor may not provide equivalent serum drug exposure as with continuous intravenous infusion, the clinical relevance of the difference is unknown. Nevirapine is well absorbed during labor, and sufficient drug for prophylaxis against perinatal transmission crosses the placenta if an oral dose is administered to the mother at least 1 hour before delivery. Placental transfer of reverse transcriptase inhibitors is good, whereas preliminary data suggest that protease inhibitors do not cross the placenta well. The use of antiretrovirals during pregnancy is becoming increasingly common, although their safety, toxicity, and teratogencity in pregnancy have not been well described. Normal growth and development have a profound impact on the pharmacokinetics of antiretrovirals in newborns and infants. Washout elimination of transplacentally acquired drug is slow. The pattern of increase in drug clearance over time will depend on the specific elimination pathway for the agent. Dosing regimens must take into account developmental changes in clearance and appropriate scaling for size. Adherence to antiretroviral regimens is a critical factor in determining the success of prophylactic and therapeutic regimens and is made difficult by the inability of infants to swallow pills and capsules.

Administration, Oral↗
PubMed2000

Prognostic factors after non-Hodgkin lymphoma in patients infected with the human immunodeficiency virus: Aquitaine Cohort, France, 1986-1997. Groupe d'Epidémiologie Clinique du SIDA en Aquitaine (GECSA).

BACKGROUND: The prognosis for survival of patients infected with the human immunodeficiency virus (HIV) who develop non-Hodgkin lymphoma (NHL) usually is considered to be poor. To the authors' knowledge the impact of highly active antiretroviral therapy, recently introduced in HIV disease case management, has not yet been studied in such circumstances. METHODS: All cases of NHL prospectively diagnosed between January 1986 and December 1997 among patients followed in the Aquitaine Cohort were reviewed. The Kaplan-Meier method and the proportional hazards model were used for statistical analysis. RESULTS: One hundred one NHL diagnoses were validated during the 12-year study period. The median proportional hazards cell count at the time of diagnosis of NHL was 112/mm(3). Histologic findings (Working Formulation classification) were: intermediate grade (N = 23), high grade (N = 61), other (N = 7), and undetermined (N = 10). In 56% of cases, staging classification was Ann Arbor Stage IV. Approximately 73% of patients received a specific NHL chemotherapy. During follow-up, 44% were treated with nucleoside reverse transcriptase inhibitors (NRTIs) alone and 18% with triple therapy including a protease inhibitor (PI). The median survival was 6.0 months. In multivariate analysis, after adjusting for age, year of NHL diagnosis, histologic type, medical center, and transmission category, the following factors recorded at the time of diagnosis of NHL were indicative of an increasing risk of death: CD4+ count </= 50/mm(3) (relative hazard [RH: 2.4, 95% confidence interval [95% CI], 1.2-4.7), hemoglobin </= 10 g/dL (RH: 2.1, 95% CI, 1.1-4.0), and Ann Arbor Stage IV (RH: 2.0, 95% CI, 1.2-3.6). Antiretroviral therapy after the diagnosis of NHL was associated with survival: NRTIs (RH: 0.27, 95% CI, 0.13-0.53) and NRTIs plus PI (RH: 0.08, 95% CI, 0.03-0.21). CONCLUSIONS: Although recently introduced and prescribed, antiretroviral therapy including PIs already has improved the survival of HIV-infected patients with NHL significantly.

Adult↗
PubMed1998

Effect of antiretroviral therapy and viral load on the perceived risk of HIV transmission and the need for safer sexual practices.

BACKGROUND: Dramatic reductions in plasma HIV RNA levels are possible with current antiretroviral regimens; the effect of potent therapies and "undetectable" viral load on the perceived risk of HIV transmission and need for safer practices remains unknown. METHODS: A questionnaire was developed to examine perceptions of HIV transmission risk and need for safer practices with unprotected anal, vaginal, and oral sex and intravenous drug use with needle sharing for HIV-discordant couples in which the HIV-infected partner was receiving no therapy, was receiving reverse transcriptase inhibitor therapy, and protease inhibitor (PI)-based therapy with viral load "undetectable". This was applied anonymously to 147 unselected HIV-infected individuals attending a university-based HIV clinic. RESULTS: Almost all respondents believed that all sexual activities except oral sex were "very risky" and that safer practices were "extremely important" for those not receiving antiretroviral agents. Significantly fewer considered that anal or vaginal sex was "very risky" for those receiving PI therapy (90.9% and 86.0%, respectively), and fewer thought that safer practices for anal or vaginal sex were "very important" for those receiving PI therapy (93.0% and 91.6%, respectively). In total, 20.4% thought the risk of HIV transmission for at least one activity was reduced for those receiving PI therapy, and 19.0% believed that the need for safer practices was reduced by PI therapy. CONCLUSION: A small but significant proportion of HIV-infected people perceive the need for safer practices to be reduced during antiretroviral therapy, particularly those containing PIs. Even if the risk is truly reduced, the importance of safer practices should be conveyed consistently and terms such as "undetectable" to describe HIV RNA responses should be avoided.

Anti-HIV Agents↗
PubMed2004

A randomized open-label study of immediate versus delayed polylactic acid injections for the cosmetic management of facial lipoatrophy in persons with HIV infection.

BACKGROUND: Polylactic acid (PLA, New-Fill; Medifill, London, UK and Dermic Labs, a division of Eventis, Strasbourg, France) injections into the deep dermis increase fibroblast numbers and collagen production. The substance is widely used in medical applications including cosmetic procedures. METHODS: HIV-positive individuals with facial lipoatrophy (based on physician assessment) were randomized to immediate (weeks 0, 2 and 4) or delayed (weeks 12, 14 and 16) PLA given as three bilateral injections 2 weeks apart into the deep dermis overlying the buccal fat pad. Assessments included facial ultrasound, visual analogue scales, the Hospital Anxiety and Depression Scale (HADS) and assessment using photographs at weeks 0, 12 and 24. RESULTS: All 30 patients completed 24 weeks of treatment. The median age of the patients was 41 years, with a mean of 80 months of nucleoside reverse transcriptase inhibitor (NRTI) therapy and a mean of 44 months of prior protease inhibitor (PI) therapy. The median CD4 count was 428-460 cells/microL, with 47% of patients in the immediate-treatment group and 93% of patients in the delayed-treatment groups with <50 HIV-1 RNA copies/mL at baseline. No differences in immunological, virological, biochemical, haematological or metabolic parameters emerged during the study. Injections were well tolerated with only two adverse events (cellulitis and bruising) recorded, one of which delayed treatment by 1 week. There were no discontinuations. Patient visual analogue assessments, photographic assessments, and anxiety and depression scores improved with treatment. At week 12, immediate-treatment patients had significantly better visual analogue scores (7 vs. 1, P<0.001) and lower anxiety scores (6 vs. 9, P=0.056) than delayed-treatment patients. Benefits on visual analogue and HADS scores persisted until week 24. CONCLUSIONS: PLA injections led to improvements in patient self-perception, anxiety and depression scores in individuals with facial lipoatrophy. Adverse events were uncommon. The benefits of PLA persisted for at least 18 weeks beyond the last injection.

Administration, Cutaneous↗
PubMed1997

Activities of the human immunodeficiency virus type 1 (HIV-1) protease inhibitor nelfinavir mesylate in combination with reverse transcriptase and protease inhibitors against acute HIV-1 infection in vitro.

Nelfinavir mesylate (formerly AG1343) is a potent and selective, nonpeptidic inhibitor of human immunodeficiency virus type 1 (HIV-1) protease that was discovered by protein structure-based design methodologies. We evaluated the antiviral and cytotoxic effects of two-drug combinations of nelfinavir with the clinically approved antiretroviral therapeutics zidovudine (ZDV), lamivudine (3TC), dideoxycytidine (ddC; zalcitabine), stavudine (d4T), didanosine (ddI), indinavir, saquinavir, and ritonavir and a three-drug combination of nelfinavir with ZDV and 3TC against an acute HIV-1 strain RF infection of CEM-SS cells in vitro. Quantitative assessment of drug interaction was evaluated by a universal response surface approach (W. R. Greco, G. Bravo, and J. C. Parsons, Pharm. Rev. 47:331-385, 1995) and by the method of M. N. Prichard and C. Shipman (Antiviral Res. 14:181-206, 1990). Both analytical methods yielded similar results and showed that the two-drug combinations of nelfinavir with the reverse transcriptase inhibitors ZDV, 3TC, ddI, d4T, and ddC and the three-drug combination with ZDV and 3TC resulted in additive to statistically significant synergistic interactions. In a similar manner, the combination of nelfinavir with the three protease inhibitors resulted in additive (ritonavir and saquinavir) to slightly antagonistic (indinavir) interactions. In all combinations, minimal cellular cytotoxicity was observed with any drug alone and in combination. These results suggest that administration of combinations of the appropriate doses of nelfinavir with other currently approved antiretroviral therapeutic agents in vivo may result in enhanced antiviral activity with no associated increase in cellular cytotoxicity.

Cell Survival↗
PubMed2002

Hepatic but not intestinal CYP3A4 displays dose-dependent induction by efavirenz in humans.

OBJECTIVE: The capacity of the non-nucleoside reverse transcriptase inhibitor efavirenz to induce either liver CYP3A4 or intestinal CYP3A4, or both, as well as intestinal P-glycoprotein, was evaluated in healthy volunteers during and after a 10-day treatment course with two different daily doses. METHODS: Cohorts of 12 healthy subjects were randomized (2:1) to receive either efavirenz or placebo orally for 10 days. The first cohort received 200 mg efavirenz and the second cohort received 400 mg efavirenz daily. Liver CYP3A4 activity was evaluated on 9 different occasions with use of the erythromycin breath test (ERMBT). Intestinal biopsy specimens were obtained before the first dose of efavirenz and on the day after administration of the last dose to measure intestinal CYP3A4 and P-glycoprotein contents by immunoblotting. Efavirenz plasma levels were measured by HPLC, and pharmacokinetic parameters were determined by standard noncompartmental methods. RESULTS: Efavirenz significantly increased the mean ERMBT result in a dose- and time-dependent manner, with a 55% mean induction at 400 mg and a 33% mean induction at 200 mg (P <.01, compared with placebo for each treatment). The efavirenz AUC on day 10 correlated with the magnitude of induction (day 11/day 1 ERMBT ratio) when the two dose groups were combined (r = 0.509; P =.04). In contrast, efavirenz treatment had no detectable effect on intestinal CYP3A4 or P-glycoprotein. CONCLUSIONS: Efavirenz is an inducer of liver CYP3A4 in healthy volunteers, and interpatient differences in magnitude of induction is partly explained by variation in systemic drug exposure. However, efavirenz did not appear to induce intestinal CYP3A4 or intestinal P-glycoprotein. These results suggest that drug interactions caused by induction of CYP3A4 can be liver specific.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2005

Long-term benefits of highly active antiretroviral therapy in Senegalese HIV-1-infected adults.

OBJECTIVES: To assess the long-term survival, as well as the immunologic and virologic effectiveness, adherence, and drug resistance, in HIV-infected patients receiving highly active antiretroviral therapy (HAART) in one of the oldest and best-documented African cohorts. METHODS: A prospective observational cohort study included the first 176 HIV-1-infected adults followed in the Senegalese government-sponsored antiretroviral therapy initiative launched in August 1998. Patients were followed for a median of 30 months (interquartile range, 21-36 months). HAART comprised 2 nucleoside reverse transcriptase inhibitors and either 1 protease inhibitor or 1 nonnucleoside reverse transcriptase inhibitor. RESULTS: At baseline, 92% of patients were antiretroviral naive and 82% had AIDS; the median CD4 count was 144 cells/mm, and median viral load was 202,368 copies/mL. The survival probability was high (0.81 at 3 years; 95% CI, 0.74-0.86) and was independently related to a baseline hemoglobin level <10 g/dL and a Karnofsky score <90%. Antiviral efficacy was consistently observed during the 3 years of treatment (-2.5 to -3.0 log10 copies/mL; 60-80% of patients with viral load <500 copies/mL) and the CD4 count increase reached a median of 225 cells/mm. Most patients reported good adherence (80-90%). The emergence of drug resistance was relatively rare (12.5%). CONCLUSION: This study shows that clinical and biologic results similar to those seen in Western countries can be achieved and sustained during the long term in Africa.

Adult↗
PubMed2005

Time trends in primary resistance to HIV drugs in the United Kingdom: multicentre observational study.

OBJECTIVE: To examine whether the level of primary resistance to HIV drugs is increasing in the United Kingdom. DESIGN: Multicentre observational study. SETTING: All virology laboratories in the United Kingdom carrying out tests for HIV resistance as part of routine clinical care. PARTICIPANTS: 2357 people infected with HIV who were tested for resistance before receiving antiretroviral therapy. MAIN OUTCOME MEASURE: Prevalence of drug resistance on basis of the Stanford genotypic interpretation system. RESULTS: Over the study period (February 1996 to May 2003), 335 (14.2%, 95% confidence interval 12.8% to 15.7%) samples had mutations that conferred resistance to one or more antiretroviral drugs (9.3% high level resistance, 5.9% medium level resistance). The prevalence of primary resistance has increased markedly over time, although patterns are specific to drug class; the largest increase was for non-nucleoside reverse transcriptase inhibitors. In 2002-3, the prevalence of resistance to any antiretroviral drug to nucleoside or nucleotide reverse transcriptase inhibitors, to non-nucleoside reverse transcriptase inhibitors, or to protease inhibitors was 19.2% (15.7% to 23.2%), 12.4% (9.5% to 15.9%), 8.1% (5.8% to 11.1%), and 6.6% (4.4% to 9.3%), respectively. The risk of primary resistance was only weakly related to most demographic and clinical factors, including ethnicity and viral subtype. CONCLUSIONS: The United Kingdom has one of the highest reported rates of primary resistance to HIV drugs worldwide. Prevalence seems still to be increasing and is high in all demographic subgroups.

Adolescent↗
PubMed2006

Selection and persistence of non-nucleoside reverse transcriptase inhibitor-resistant HIV-1 in patients starting and stopping non-nucleoside therapy.

BACKGROUND: Understanding the selection and decay of drug-resistant HIV-1 variants is important for designing optimal antiretroviral therapy. OBJECTIVE: To develop a high-throughput, real-time reverse transcriptase (RT) polymerase chain reaction (PCR) assay to quantify non-nucleoside reverse transcriptase inhibitor (NNRTI)-resistant variants K103N (AAT or AAC alleles) at frequencies as low as 0.1%, and to apply this to monitor these variants before, during, and after NNRTI therapy. METHODS: HIV-1 RNA in longitudinal plasma samples obtained from patients starting and stopping NNRTI therapy was converted to cDNA and the target sequence region amplified and quantified by real-time PCR. Approximately 10 copies/reaction provided a template for a second round of PCR using primers that discriminated between the mutant and wild-type alleles. Amplification specificity was confirmed by thermal denaturation analysis. RESULTS: Frequencies of 103N similar to assay background (0.029%) were observed in longitudinal samples from 9 of 12 treatment-naive patients; three patients had transient increases in 103N frequency to a range of 0.21-0.48%, which was 7-16.5 times assay background. Analysis of longitudinal plasma samples from six NNRTI-experienced patients showed three patterns: persistence of 103N variants after stopping NNRTI therapy, codon switching of 103N between AAC and AAT during NNRTI therapy, and decay of 103N variants to below assay background after cessation of NNRTI therapy. CONCLUSIONS: Allele-specific RT-PCR quantified the emergence and decay of drug-resistant variants in patients over a broad range of frequencies (0.1-100%). The rate of decay of K103N variants after stopping NNRTI therapy was highly variable.

Adult↗
PubMed1996

Complexes of HIV-1 reverse transcriptase with inhibitors of the HEPT series reveal conformational changes relevant to the design of potent non-nucleoside inhibitors.

Crystal structures of HIV-1 reverse transcriptase (RT) complexed with a range of chemically diverse non-nucleoside inhibitors (NNIs) have shown a single pocket in which the inhibitors bind and details of the inhibitor-protein interactions. To delineate the structural requirements for an effective inhibitor, we have determined the structures of three closely related NNIs which vary widely in their potencies. Crystal structures of HIV-1 RT complexed with two very potent inhibitors, MKC-442 and TNK-651, at 2.55 angstroms resolution complement our previous analysis of the complex with the less effective inhibitor, HEPT. These structures reveal conformational changes which correlate with changes in potency. We suggest that a major determinant of increased potency in the analogues of HEPT is an improved interaction between residue Tyr181 in the protein and the 6-benzyl ring of the inhibitors which stabilizes the structure of the complex. This arises through a conformational switching of the protein structure triggered by the steric bulk of the 5-substituent of the inhibitor pyrimidine ring.

Antiviral Agents↗
PubMed2004

In vitro studies of the effects of HAART drugs and excipients on activity of digestive enzymes.

PURPOSE: Side effects of diarrhea and steatorrhea diminish the therapeutic value of highly active antiretroviral therapy (HAART). We report in vitro studies of the effect of HAART drugs on the activity of pancrelipase, trypsin, and enterokinase and restoration of activity by subsequent addition of excess pancrelipase or colipase. METHODS: Commercial formulations of sixteen HAART drug formulations with solvent and four excipients were mixed with substrate. Activity of pancrelipase was recorded after addition of the enzyme; restoration of activity was monitored after addition of excess pancrelipase or colipase to the reaction mixture. RESULTS: Five protease inhibitors (Agenerase solution, Agenerase capsules, Norvir, Viracept, Kaletra, and Fortovase) and the excipient TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate) inhibited lipase significantly at or below physiological concentrations. Neither nucleoside reverse transcriptase inhibitors nor non-nucleoside reverse transcriptase inhibitors showed significant lipase inhibition at physiological levels. Addition of excess pancrelipase to the medium completely reversed inhibition by Agenerase, Fortovase, Norvir, and TPGS and reactivated lipase; it diminished inhibition by Kaletra and Viracept but did not completely restore activity. Addition of colipase reversed inhibition by Agenerase solution, Agenerase capsules, and TPGS; inhibition by Kaletra and Fortovase recovered slightly. No compounds tested inhibited trypsin or enterokinase. CONCLUSIONS: These results justify evaluating protocols involving coadministration of buffered pancrelipase with protease inhibitors to reduce or eliminate diarrhea and steatorrhea in individuals being treated for HIV.

Antiretroviral Therapy, Highly Active↗
PubMed2000

Current approaches to treatment for HIV-1 infection.

The last 3 years have seen a dramatic fall in mortality and morbidity from HIV infection. Four factors have contributed to this: an improved understanding of the pathogenesis of HIV infection; the availability of tests that could measure plasma viral burden; the development of new and more powerful drugs such as the protease and non-nucleoside reverse transcriptase inhibitors; and the completion of large clinical endpoint trials that conclusively demonstrated that potent antiretroviral combinations significantly delayed the progression of HIV disease and improved survival. Typical antiretroviral regimen now consist of at least three agents: one or two protease inhibitors or a non-nucleoside reverse transcriptase inhibitor combined with two nucleoside analogs. The goal of therapy is to reduce measurable plasma viral burden to undetectable levels. Viral load testing has made it possible to individualize therapy and to more accurately determine the best time to initiate or change therapy, long before declining CD4+ counts would have given evidence of active viral replication. However, despite the impressive progress to date, there remain significant shortcomings with current treatment. Even with the most potent regimens available, there exists a proportion of patients (perhaps 20 - 50% of treated individuals) who fail to have complete and durable virologic responses to therapy. The shortcomings of current regimens are particularly evident in patients with high plasma HIV-1 RNA levels, extensive prior treatment, and advanced disease. Complexity, short- and long-term toxicities, cross-resistance, and drug-drug interactions all complicate current regimens. Viral resistance is increasingly encountered in clinical practice and transmission of resistant virus is well-documented. In addition, there remain concerns about the ability of the virus to evade current therapies, whether in viral reservoirs in non-lymphoid compartments or in lymphoid tissue, such as resting memory T cells. Thus there remains a need for new therapies as well as new strategies using existing drugs.

HIV Infections↗
PubMed1999

The picture of future therapy.

Highly active antiretroviral therapy (HAART) consisting of 2 nucleoside reverse transcriptase inhibitors (NRTIs) in combination with a protease inhibitor (PI) or a non nucleoside reverse transcriptase inhibitor (NNRTI) is now regarded as the standard of care in the treatment of HIV infection. However, over the next few years it is anticipated that clinician will become increasingly concerned with the quality of clinical data, the cost of treatment and virological failure. Several causes of virological failure have already been identified including compliance, toxicity, pharmacokinetic interactions, resistance and lack of potency. Many studies have been performed to investigate new combination regimens and new drugs to find solutions to these problems. In addition, new targets for antiviral drugs are also being investigated.

Drug Therapy, Combination↗
PubMedDate not supplied

Reduced antiretroviral drug susceptibility among patients with primary HIV infection.

CONTEXT: The transmission of drug-resistant human immunodeficiency virus (HIV) has been documented, but the prevalence of such transmission is unknown. OBJECTIVE: To assess the spectrum and frequency of antiretroviral susceptibility among subjects with primary HIV infection. DESIGN, SETTING, AND PATIENTS: Retrospective analysis of 141 subjects identified from clinical research centers in 5 major metropolitan areas, enrolled from 1989 to 1998, with HIV seroconversion within the preceding 12 months and no more than 7 days' prior antiretroviral (ARV) therapy. MAIN OUTCOME MEASURES: Phenotypic and genotypic ARV susceptibility of HIV from plasma samples. RESULTS: The transmission of drug-resistant HIV as assessed by a greater than 10-fold reduction in ARV susceptibility to 1 or more drugs was observed in 3 (2%) of 141 subjects, including to a nonnucleoside reverse transcriptase inhibitor in 1 patient and to a nucleoside reverse transcriptase inhibitor and a protease inhibitor in 2 patients. Population-based sequence analysis of these 3 samples identified multidrug-resistance mutations in reverse transcriptase (M184V, T215Y, K219K/R) and protease (L101/V, K20R, M361, M46I, G48V, L63P, A71T, V771, V82T, 184V, L90M) in the 2 latter patient samples, along with numerous polymorphisms. A reduction in susceptibility of greater than 2.5- to 10-fold to 1 or more drugs was observed in viral isolates from 36 patients (26%). Sequence analysis of these 36 samples identified well-characterized drug resistance mutation in reverse transcriptase and protease in only 1 of these patients. CONCLUSIONS: Reductions in drug susceptibility of more than 10-fold were rare among this cohort of recently HIV-infected subjects and were distributed among each of the 3 major classes of ARV drugs tested. Reductions in susceptibility of more than 2.5- to 10-fold to certain ARV drugs of unknown clinical significance were highly prevalent among newly infected patients. Resistance testing may be warranted to monitor the frequency of drug resistance over time and to assess the potential for geographic variability.

Adolescent↗