Acquired Immunodeficiency Syndrome: Richman DD

Yeni PG, Hammer SM, Carpenter CC, Cooper DA, Fischl MA, Gatell JM, Gazzard BG, Hirsch MS, Jacobsen DM, Katzenstein DA, Montaner JS, Richman DD, Saag MS, Schechter M, Schooley RT, Thompson MA, Vella S, Volberding PA. · Hôpital Bichat-Claude Bernard, Department of Infectious Diseases, 46 Rue Henri-Huchard, Paris, Cedex 18 France 75877. · JAMA. · Pubmed #12095387 No free full text.

Abstract: OBJECTIVE: New information warrants updated recommendations for the 4 central issues in antiretroviral therapy: when to start, what drugs to start with, when to change, and what to change to. These updated recommendations are intended to guide practicing physicians actively involved in human immunodeficiency virus (HIV)- and acquired immunodeficiency syndrome (AIDS)-related care. PARTICIPANTS: In 1995, physicians with specific expertise in HIV-related basic science and clinical research, antiretroviral therapy, and HIV patient care were invited by the International AIDS Society-USA to serve on a volunteer panel. In 1999, others were invited to broaden international representation. The 17-member panel met regularly in closed meetings between its last report in 2000 and April 2002 to review current data. The effort was sponsored and funded by the International AIDS Society-USA, a not-for-profit physician education organization. EVIDENCE AND CONSENSUS PROCESS: The full panel was convened in late 2000 and assigned 7 section committees. A section writer and 3 to 5 section committee members (each panel member served on numerous sections) identified relevant evidence and prepared draft recommendations. Basic science, clinical research, and epidemiologic data from the published literature and abstracts from recent (within 2 years) scientific conferences were considered by strength of evidence. Extrapolations from basic science data and expert opinion of the panel members were included as evidence. Draft sections were combined and circulated to the entire panel and discussed in a series of full-panel conference calls until consensus was reached. Final recommendations represent full consensus agreement of the panel. CONCLUSIONS: Because of increased awareness of the activity and toxicity of current drugs, the threshold for initiation of therapy has shifted to a later time in the course of HIV disease. However, the optimal time to initiate therapy remains imprecisely defined. Availability of new drugs has broadened options for therapy initiation and management of treatment failure, which remains a difficult challenge.

Lange JM, Richman DD. · No affiliation provided · Antivir Ther. · Pubmed #10682122 No free full text.

This publication has no abstract.

Eron JJ, Park JG, Haubrich R, Aweeka F, Bastow B, Pakes GE, Yu S, Wu H, Richman DD, Anonymous00046. · Division of Infectious Diseases, School of Medicine, University of North Carolina at Chapel Hill, 130 Mason Farm Rd., Bio-Informatics Building CB No. 7215, Chapel Hill, NC 27599-7215, USA. · Antimicrob Agents Chemother. · Pubmed #19307363 No free full text.

Abstract: The activities of protease inhibitors in vivo may depend on plasma concentrations and viral susceptibility. This nonrandomized, open-label study evaluated the relationship of the inhibitory quotient (IQ [the ratio of drug exposure to viral phenotypic susceptibility]) to the human immunodeficiency virus type 1 (HIV-1) viral load (VL) change for ritonavir-enhanced protease inhibitors (PIs). Subjects on PI-based regimens replaced their PIs with ritonavir-enhanced indinavir (IDV/r) 800/200 mg, fosamprenavir (FPV/r) 700/100 mg, or lopinavir (LPV/r) 400/200 mg twice daily. Pharmacokinetics were assessed at day 14; follow-up lasted 24 weeks. Associations between IQ and VL changes were examined. Fifty-three subjects enrolled, 12 on IDV/r, 33 on FPV/r, and 8 on LPV/r. Median changes (n-fold) (FC) of 50% inhibitory concentrations (IC(50)s) to the study PI were high. Median 2-week VL changes were -0.7, -0.1, and -1.0 log(10) for IDV/r, FPV/r, and LPV/r. With FPV/r, correlations between the IQ and the 2-week change in VL were significant (Spearman's r range, -0.39 to -0.50; P < or = 0.029). The strongest correlation with response to FPV/r was the IC(50) FC (r = 0.57; P = 0.001), which improved when only adherent subjects were included (r = 0.68; P = 0.001). In multivariable analyses of the FPV/r arm that included FC, one measure of the drug concentration, corresponding IQ, baseline VL, and CD4, the FC to FPV was the only significant predictor of VL decline (P < 0.001). In exploratory analyses of all arms, the area under the concentration-time curve IQ was correlated with the week 2 VL change (r = -0.72; P < 0.001). In conclusion, in PI-experienced subjects with highly resistant HIV-1, short-term VL responses to RTV-enhanced FPV/r correlated best with baseline susceptibility. The IQ improved correlation in analyses of all arms where a greater range of virologic responses was observed.

Strain MC, Little SJ, Daar ES, Havlir DV, Gunthard HF, Lam RY, Daly OA, Nguyen J, Ignacio CC, Spina CA, Richman DD, Wong JK. · Department of Physics, University of California at San Diego, La Jolla, California, USA. · J Infect Dis. · Pubmed #15809898 No free full text.

Abstract: Patients in whom virologic suppression is achieved with highly active antiretroviral therapy (HAART) retain long-lived cellular reservoirs of human immunodeficiency virus type 1 (HIV-1); this retention is an obstacle to sustained control of infection. To assess the impact that initiating treatment during primary HIV-1 infection has on this cell population, we analyzed the decay kinetics of HIV-1 DNA and of infectivity associated with cells activated ex vivo in 27 patients who initiated therapy before or <6 months after seroconversion and in whom viremia was suppressed to <50 copies/mL. The clearance rates of cellular reservoirs could not be distinguished by these techniques (median half-life, 20 weeks) during the first year of HAART. The clearance of HIV-1 DNA slowed significantly during the subsequent 3 years of treatment (median half-life, 70 weeks), consistent with heterogeneous cellular reservoirs being present. Total cell-associated infectivity (CAI) after 1 year of treatment was undetectable (<0.07 infectious units/million cells [IUPM]) in most patients initiating treatment during primary infection either before (9/9) or <6 months after (6/8) seroconversion. In contrast, all 17 control patients who initiated HAART during chronic infection retained detectable CAI after 3-6 years of treatment (median reservoir size, 1.1 IUPM; P<.0005). These results suggest that treatment <6 months after seroconversion may facilitate long-term control of cellular reservoirs that maintain HIV-1 infection during treatment.

Bennett KK, DeGruttola VG, Marschner IC, Havlir DV, Richman DD. · SDAC, Harvard School of Public Health, Boston, Massachusetts 02115, USA. · J Acquir Immune Defic Syndr. · Pubmed #12352146 No free full text.

Abstract: CD4 T-cell recovery with potent antiretroviral therapy varies considerably among HIV-1-infected patients. Data from two studies that enrolled subjects at different stages of disease progression were retrospectively combined. This analysis assessed the association between patient-specific factors and three measures of CD4 T-cell recovery after the initiation of triple-drug therapy: overall changes in CD4 cell counts; changes in CD4 cell counts during the first 8 weeks (phase I); and changes in CD4 cell counts during weeks 8-24 (phase II). Higher initial HIV-1 RNA values corresponded to greater increases in overall and phase I changes in mean CD4 cell counts, particularly among subjects with less advanced disease. In the overall and phase II cases, those subjects with suppressed HIV RNA levels had consistently higher increases in mean CD4 cell counts across both baseline HIV-1 RNA levels and CD4 cell counts than did the respective unsuppressed group. Based on a multivariate model, increases in mean phase I CD4 cell counts corresponded to higher log baseline HIV-1 RNA levels (p =.0001) and log changes in HIV-1 RNA levels at week 4 (p =.03). Patients with earlier stages of disease (p =.0001) and females (p =.01) had higher increases in phase I changes. Phase II CD4 cell counts did not depend solely on baseline HIV-1 RNA levels and CD4 cell counts but on their interaction (p =.0001) as well as on achieving virologic suppression (p =.0009).

Hanna GJ, Johnson VA, Kuritzkes DR, Richman DD, Brown AJ, Savara AV, Hazelwood JD, D'Aquila RT. · Infectious Disease Unit and AIDS Research Center, Massachusetts General Hospital, Charlestown, MA 02129, USA. · J Infect Dis. · Pubmed #10720511 No free full text.

Abstract: Resistance mutations selected in reverse transcriptase (RT) by incompletely suppressive therapy with combination zidovudine and didanosine with or without nevirapine were identified in 141 human immunodeficiency virus type 1 isolates from peripheral blood mononuclear cells of 57 individuals in the AIDS Clinical Trials Group protocol 241. After prolonged treatment (16-48 weeks), the most common nevirapine-selected mutations were RT 181C (15/30 isolates [50%]), 190A (15/30 [50%]), and 101E (9/30 [30%]). RT 103N and 188L, which individually confer cross-resistance to all nonnucleoside RT inhibitors, were seen in a minority of viruses (6/30 [20%] and 4/30 [13%], respectively). Didanosine-resistance mutations arose rarely. A newly recognized mutation, RT 44D, was selected by the nucleosides. Two distinct zidovudine-resistance mutational patterns were noted. Mutations selected during treatment with zidovudine, didanosine, and nevirapine differed among individuals and changed over time. Resistance testing is necessary to identify which mutations are selected by nevirapine-containing combinations.

Precious HM, Günthard HF, Wong JK, D'Aquila RT, Johnson VA, Kuritzkes DR, Richman DD, Leigh Brown AJ. · Centre for HIV Research, University of Edinburgh, Scotland. · AIDS. · Pubmed #10714565 No free full text.

Abstract: OBJECTIVE: To determine whether analysis of sequence variation in reverse transcriptase at baseline can explain differences in response to combination antiretroviral therapy. METHODS: Amino acid sequences of reverse transcriptase obtained from baseline isolates from 55 patients included in a trial of zidovudine and didanosine versus zidovudine/didanosine/nevirapine (ACTG241) were analysed. Simple and multiple linear regression were used to determine the relationship between numbers and identity of mutations at baseline and virological response after 8 and 48 weeks. RESULTS: Numbers of baseline zidovudine resistance mutations were predictive of short-term response (week 8). Amino acid identity at position 215 explained > 20% of the variation in response at week 8, but less at week 48. Multiple regression identified the combinations: 215 + 44 and 41 + 202, each of which explained about 30% of the variation in week 8 response. A model incorporating amino acids 214 + 215 + 60 + 202 + baseline viral load explained > 40% of the variation in response at week 48. Unexpectedly, the mutant combination 601 + 215Y/F responded threefold better than 60V + 215Y/F over 48 weeks. CONCLUSIONS: Use of clinical data to analyse virological response to combination therapy has revealed effects of baseline amino acid mutations at sites not previously identified as being important in antiretroviral resistance. Predictors of long-term responses were different from those involved in the short term and may require more complex analysis.

Brown AJ, Günthard HF, Wong JK, D'Aquila RT, Johnson VA, Kuritzkes DR, Richman DD. · Centre for HIV Research, University of Edinburgh, Edinburgh EH9 3JN, Scotland. · J Infect Dis. · Pubmed #10479129 No free full text.

Abstract: Many amino acid (aa) sites in reverse transcriptase (RT) have been implicated in resistance to nucleoside (NRTI) and nonnucleoside antiretrovirals. Interactions between these in response to combination therapy remain poorly understood. In a trial (ACTG 241) of zidovudine/didanosine (ddI) versus zidovudine/ddI/nevirapine in nucleoside-experienced patients, baseline sequence data from the RT coding region was analyzed from 55 individuals. Sequences were clustered by use of a parsimony method and the virological responses (ratio of baseline viral load to viral load after of therapy) for each cluster were analyzed at week 8 and week 48. Both clusters and genotype at aa 215 were significantly associated with virological response at both time points, whereas viral load showed a stronger association with sequence clusters. Sequence clusters identified one group of patients who never developed high-level resistance to NRTIs despite prior nucleoside exposure and poor suppression of viral replication.

Koelsch KK, Liu L, Haubrich R, May S, Havlir D, Günthard HF, Ignacio CC, Campos-Soto P, Little SJ, Shafer R, Robbins GK, D'Aquila RT, Kawano Y, Young K, Dao P, Spina CA, Richman DD, Wong JK. · University of California, San Diego, USA. · J Infect Dis. · Pubmed #18248304 No free full text.

Abstract: BACKGROUND: In patients infected with human immunodeficiency virus type 1 (HIV-1), HIV-1 DNA persists during highly active antiretroviral treatment, reflecting long-lived cellular reservoirs of HIV-1. Recent studies report an association between HIV-1 DNA levels, disease progression, and treatment outcome. However, HIV-1 DNA exists as distinct molecular forms that are not distinguished by conventional assays. METHODS: We analyzed HIV-1 RNA levels in plasma, CD4 cell counts, and levels of integrated and nonintegrated HIV-1 DNA in peripheral blood mononuclear cells (PBMCs) from patients with early or chronic infection before and during antiretroviral treatment. We also studied HIV-1 DNA decay in primary CD4 T cells infected in vitro. HIV-1 DNA was analyzed using an assay that is unaffected by the location of HIV-1 integration sites. RESULTS: HIV-1 RNA levels and total HIV-1 DNA levels decayed rapidly in patients during receipt of suppressive antiretroviral therapy. Ratios of total HIV-1 DNA levels to integrated HIV-1 DNA levels were high before initiation of therapy but diminished during therapy. Levels of linear nonintegrated HIV-1 DNA decayed rapidly in vitro (t (1/2) = 1- 4.8 days). CONCLUSION: Total HIV-1 DNA decays rapidly with suppression of virus replication in vivo. Clearance of HIV-1 DNA during the first 6 months of therapy reflects a disproportionate loss of nonintegrated HIV-1 DNA genomes, suggesting that levels of total HIV-1 DNA in PBMCs after prolonged virus suppression largely represent integrated HIV-1 genomes.

Yang OO, Daar ES, Jamieson BD, Balamurugan A, Smith DM, Pitt JA, Petropoulos CJ, Richman DD, Little SJ, Brown AJ. · 37-121 Center for Health Sciences, Division of Infectious Diseases, 10833 LeConte Ave., UCLA Medical Center, Los Angeles, CA 90095, USA. · J Virol. · Pubmed #15613314 links to  free full text

Abstract: Sequential infection with different strains of human immunodeficiency virus type 1 (HIV-1) is a rarely identified phenomenon with important implications for immunopathogenesis and vaccine development. Here, we identify an individual whose good initial control of viremia was lost in association with reduced containment of a superinfecting strain. Subject 2030 presented with acute symptoms of HIV-1 infection with high viremia and an incomplete seroconversion as shown by Western blotting. A low set point of viremia (approximately 1,000 HIV-1 copies/ml) was initially established without drug therapy, but a new higher set point (approximately 40,000 HIV-1 copies/ml) manifested about 5 months after infection. Drug susceptibility testing demonstrated a multidrug-resistant virus initially but a fully sensitive virus after 5 months, and an analysis of pol genotypes showed that these were two phylogenetically distinct strains of virus (strains A and B). Replication capacity assays suggested that the outgrowth of strain B was not due to higher fitness conferred by pol, and env sequences indicated that the two strains had the same R5 coreceptor phenotype. Delineation of CD8+-T-lymphocyte responses against HIV-1 showed a striking pattern of decay of the initial cellular immune responses after superinfection, followed by some adaptation of targeting to new epitopes. An examination of targeted sequences suggested that differences in the recognized epitopes contributed to the poor immune containment of strain B. In conclusion, the rapid overgrowth of a superinfecting strain of HIV-1 of the same subtype raises major concerns for effective vaccine development.

Haas DW, Wilkinson GR, Kuritzkes DR, Richman DD, Nicotera J, Mahon LF, Sutcliffe C, Siminski S, Andersen J, Coughlin K, Clayton EW, Haines J, Marshak A, Saag M, Lawrence J, Gustavson J, Anne Bennett J, Christensen R, Matula MA, Wood AJ, Anonymous00294. · Division of Infectious Diseases, Vanderbilt University School of Medicine, Nashville, Tennessee 37203, USA. · HIV Clin Trials. · Pubmed #14583845 links to  free full text

Abstract: BACKGROUND: An understanding of the relationships among allelic variability and clinical outcomes will be critical if HIV-infected patients are to benefit from the explosion in knowledge in human genomics. Human DNA banks must allow future analyses while addressing confidentiality, ethical, and regulatory issues. METHOD: A multidisciplinary group of clinical investigators, ethicists, data managers, regulatory specialists, and community representatives developed Adult AIDS Clinical Trials Group (AACTG) Protocol A5128. Participants in past or present AACTG clinical trials may contribute DNA. Extraction from whole blood is performed at a central laboratory, where participants' unique identifiers are replaced by randomly assigned identifiers prior to DNA storage. To identify genotype-phenotype relationships, genetic assay results can be temporarily linked to clinical trials data. RESULTS: Institutional review boards in 21 states and Puerto Rico have approved Protocol A5128, and accrual is ongoing. Of the first 4,247 enrollees, 82% are male, 56% are white, 26% are African American, and 15% are Hispanic. Because participants may participate in multiple AACTG protocols, these represent 11,424 cases in 324 different AACTG studies and substudies, with at least 100 participants from 24 different studies. Studies exploring specific genotype-phenotype relationships are underway. CONCLUSION: The AACTG DNA bank will be an important resource for genomic discovery relevant to HIV therapy.

Richman DD, Wrin T, Little SJ, Petropoulos CJ. · Department of Pathology, Veterans Affairs San Diego Healthcare System and the University of California at San Diego, La Jolla, CA 92093-0679, USA. · Proc Natl Acad Sci U S A. · Pubmed #12644702 links to  free full text

Abstract: A recombinant virus assay was used to characterize in detail neutralizing antibody responses directed at circulating autologous HIV in plasma. Examining serial plasma specimens in a matrix format, most patients with primary HIV infection rapidly generated significant neutralizing antibody responses to early (0-39 months) autologous viruses, whereas responses to laboratory and heterologous primary strains were often lower and delayed. Plasma virus continually and rapidly evolved to escape neutralization, indicating that neutralizing antibody exerts a level of selective pressure that has been underappreciated based on earlier, less comprehensive characterizations. These data argue that neutralizing antibody responses account for the extensive variation in the envelope gene that is observed in the early months after primary HIV infection.

Hale P, Makgoba MW, Merson MH, Quinn TC, Richman DD, Vella S, Wabwire-Mangen F, Wain-Hobson S, Weiss RA. · Institut Necker, Faculté de Médecine Necker-Enfants Malades, 156 Rue de Vaugirard, 75015 Paris, France. · Nature. · Pubmed #11460135 No free full text.

This publication has no abstract.

Hale P, Makgoba MW, Merson MH, Quinn TC, Richman DD, Vella S, Wabwire-Mangen F, Wain-Hobson S, Weiss RA. · Institut Necker, Faculté de Médecine Necker-Enfants Malades, 156 Rue de Vaugirard, 75015 Paris, France. · Nature. · Pubmed #11460133 No free full text.

This publication has no abstract.

Zhang Z, Schuler T, Zupancic M, Wietgrefe S, Staskus KA, Reimann KA, Reinhart TA, Rogan M, Cavert W, Miller CJ, Veazey RS, Notermans D, Little S, Danner SA, Richman DD, Havlir D, Wong J, Jordan HL, Schacker TW, Racz P, Tenner-Racz K, Letvin NL, Wolinsky S, Haase AT. · Department of Microbiology, University of Minnesota Medical School, Minneapolis, MN 55455, USA. · Science. · Pubmed #10558989 links to  free full text

Abstract: In sexual transmission of simian immunodeficiency virus, and early and later stages of human immunodeficiency virus-type 1 (HIV-1) infection, both viruses were found to replicate predominantly in CD4(+) T cells at the portal of entry and in lymphoid tissues. Infection was propagated not only in activated and proliferating T cells but also, surprisingly, in resting T cells. The infected proliferating cells correspond to the short-lived population that produces the bulk of HIV-1. Most of the HIV-1-infected resting T cells persisted after antiretroviral therapy. Latently and chronically infected cells that may be derived from this population pose challenges to eradicating infection and developing an effective vaccine.

Little SJ, McLean AR, Spina CA, Richman DD, Havlir DV. · Department of Medicine, University of California San Diego, San Diego, California 92103, USA. · J Exp Med. · Pubmed #10499922 links to  free full text

Abstract: Viral dynamics were intensively investigated in eight patients with acute HIV infection to define the earliest rates of change in plasma HIV RNA before and after the start of antiretroviral therapy. We report the first estimates of the basic reproductive number (R(0)), the number of cells infected by the progeny of an infected cell during its lifetime when target cells are not depleted. The mean initial viral doubling time was 10 h, and the peak of viremia occurred 21 d after reported HIV exposure. The spontaneous rate of decline (alpha) was highly variable among individuals. The phase 1 viral decay rate (delta(I) = 0.3/day) in subjects initiating potent antiretroviral therapy during acute HIV infection was similar to estimates from treated subjects with chronic HIV infection. The doubling time in two subjects who discontinued antiretroviral therapy was almost five times slower than during acute infection. The mean basic reproductive number (R(0)) of 19.3 during the logarithmic growth phase of primary HIV infection suggested that a vaccine or postexposure prophylaxis of at least 95% efficacy would be needed to extinguish productive viral infection in the absence of drug resistance or viral latency. These measurements provide a basis for comparison of vaccine and other strategies and support the validity of the simian immunodeficiency virus macaque model of acute HIV infection.