Meet the Professor Session: Metabolic Complications of Therapy

For the 2nd day in the row, I headed over to the convention center for a 7 AM session in the rain. Why? The topic is important and Steve Grinspoon (an endocrinologist from Harvard) and Judith Aberg (from Washington University) are experts in the field. A few pearls I picked up include:

1. The HIV-associated lipodystrophy syndrome probably represents 4 overlapping entities (central fat accumulation, peripheral fat wasting, increased lipids, and insulin resistance).
2. At baseline before therapy, get fasting lipids, glucose, waist-to-hip ratios and possibly a 75 gm glucose tolerance test.
3. Free testosterone levels done correctly are the best way to evaluate for hypogonadism.

The interest in the topic was manifest by the steady stream of questions from the audience, which reflected a wide diversity of opinions about what causes and what to do about these abnormalities. The panelists stressed that answers are lacking and that good studies need to be done (i.e., ACTG studies such as the lipid-lowering study chaired by Judy and a study using metformin and/or a glitazide drug for fat problems with Steve's involvement).

HIV Slide Session II

I will try to briefly summarize several of the presentations that I found quite interesting. A study presented by Lisa Frankel (abstract #42) looked at viral evolution in a group of 10 children with levels of plasma RNA < 50 copies/ml. Although they found evidence for low level viral replication (especially in those will some viral blips), there was no evidence for evolution of resistance. The next presentation by the group from Duke (#43) found evidence for excellent immune reconstitution in children even when HAART was started in the setting of advanced immune dysfunction. In fact, immune parameters in those children were similar to or better than those in a group of children who were never sick and who had stable surrogate markers. That raised the issue of the optimal timing of treatment -- early to maximize benefit, versus later when the drugs and knowledge are better.

In another nice study by the group from the Toronto Hospital for Sick Children (#44), 28 children receiving a HAART regimen with a protease inhibitor (mostly ritonavir or nelfinavir) were evaluated for metabolic parameters. 68% had high cholesterol levels and 36% had evidence for insulin resistance. There was a suggestion of some increase in visceral fat that may have correlated with the triglyceride levels.

The final two presentations related to vaccine/transmission issues. The group from Kansas University reported on a novel HIV vaccine involving an attenuated strain of SHIV (vpu gene depleted) which appeared to offer protection to a group of 6 macaques from a highly pathogenetic strain administered intravaginally (#46). They are considering a human trial in HIV infected persons using an AZT-resistant variant of the vaccine strain administered after stopping HAART and while giving only AZT (in subjects with no history of AZT-resistant virus). Several interesting questions were asked from the audience about that approach. Finally, Stephan Smith presented data showing that the use of vaginal estrogen could protect ovariectomized female macaques from infection from intravaginal inoculation of pathogenic SIV(#47).

Summary of HIV Poster Sessions

It is always invigorating to be able to walk around and speak to the authors standing at their posters. I will try to highlight posters involving three categories; public health/testing issues, clinical issues, and antiretroviral therapy. Several posters suggested that rapid HIV tests have a role in promoting early access to HIV care (#318 and #319) and in managing occupational HIV exposures (#320). The group from Parkland (#324) documented the growing level of medical co-morbidities in a group of 335 HIV+ patients now averaging 1.92 per patient. One poster (#352) described 6 cases of hepatic steatosis/lactic acidosis in obese patients (2 deaths; 5/6 on D4T) and another (#377) reported 12 admissions for lactic acidosis over a four-year period (four deaths; 13/14 on d4T; eight in the last year). In a group of 365 patients evaluated for HIV-associated adipose redistribution syndrome by Don Kottler's group, a multivariate analysis found that female gender, low RNA, and high BMI were associated with fat accumulation (#353). D4T was the only co-variate associated with lipoatrophy. In another interesting study, nonadherence rates were found to be common and there was poor correlation between patient reports and pharmacy records (#358). Finally, two posters suggested that resistance testing was not helpful in late salvage in a group of pediatric (#365) or adult (#364) patients.

For the antiretroviral therapy summary, I will discuss the NRTIs, the NNRTIs, PIs, and then new drugs. In a study using Combivir + Ziagen as directly observed therapy in the prison setting (#331), high rates of viral suppression (using strictest criteria ITT-MEF with RNA < 50 = 60%) were achieved at 24 weeks (two hypersensitivy reactions out of 111 subjects). In a retrospective case control study looking at the impact of hydroxyurea (n = 59) when used as a part of a HAART salvage regimen, no benefit from HU was found and there was a diminished CD4 response and more thrombocytopenia (#333). Since there is a lot of interest in dual NNRTI therapy, one poster looked at experience with nevirapine and efavirenz based salvage therapy in the setting of PI failure. In 13 patients, 77% had viral load < 50 copies at five months (2/3 of the failures were NNRTI experienced). There was one rash and a low rate of increased liver enzymes (#338). Data on two-week monotherapy in a dose ranging study of DAVD was presented by Melanie Thompson (#341). At 500 mg BID, the viral load dropped by 1.46 log without development of any discernable resistance and good tolerability. That compound looks promising so far.

Several posters examined the use of amprenavir in PI experienced patients. The first looked at 128 patients who had received amprenavir for at least 24 weeks. By intent-to-treat analysis, the percent achieving viral level < 400 copies at 40 weeks among persons who had previously received one, two, three, or four PIs was 76%, 62%, 53% and 38% respectively (#329). A French group looked at the trough level IC90 ratio and the virologic response to an amprenavir-efavirenz containing regimen (#330). Boosting the amprenavir trough level with ritonavir in amp/efv containing regimens appeared to lead to a better early virologic response. Finally, another French study looked at the relationship between trough plasma levels of nelfinavir (n = 78 patients) or indinavir (n = 104 patients) and virologic response(#336). Median trough levels were significantly higher for both protease inhibitors among patients with undetectable viral levels, again underscoring the potential value of therapeutic drug monitoring in some settings.

References

• 42. Viral Evolution in Children with Plasma HIV-1 RNA levels #50 copies/ml.
  Authored by Lisa M. Frenkel, Ann J. Melvin, Gianinna M. Ellis, Shannon Devange, Wilscott E. Naugler, Ingrid Beck, Kathleen M. Mohan, Paul A. Lewis, Yang Wang, Gerald H. Learn, and James I. Mullins.

• 43. Immune Reconstitution in HIV-1 Infected Children on HAART: A Cohort Study.
  Authored by A.M. Johnston, M. E. Valentine, J. Ottinger, R. Baydo, V. Gryszowka, C. Vavro, K. Weinhold, M. St. Clair, and R. Mckinney.

• 44. Fasting Cholesterol (CL) and Triglyceride (TG) Levels and Abdominal Adipose Tissue Distribution (AATD) in Protease Inhibitor (PI)-Treated HIV-Infected Children.
  Authored by A.Bitnun, E. Sochett, P. Babyn, C. Arneson, S. Holowka, S. Read, and S. King

• 46. Macaques Immunized Orally with a Live HIV Vaccine and Challenged Vaginally with Pathogenic SHIV Six Months Later Not Only Resisted Disease but Also Gradually Eliminated DNA of the Challenge Virus.
  Authored by P. Silverstein, G.A. Mackay, S. Mukherjee, A. Kumar, Z. Li, I. Adany, and I. Narayan.

• 47. Estrogen Protects against Vaginal Transmission of SIV.
  Authored by Stephen M. Smith, Gary B. Baskin, and Preston A. Marx

• 318. Rapid HIV Tests Promote Early Entry and Retention into Healthcare.
  Authored by Sabrina R. Kendrick, Karen Kroc, Robert J. Rydman, Bernard Branson, David Withum, and Robert A Weinstein.

• 319. Rapid HIV Test Offer Fast Technique and Improve HIV Case Identification.
  Authored by Sabrina R. Kendrick, Robert J. Rydman, Karen Kroc, Bernard Branson, David Withum, and Robert A. Weinstein.

• 320. Use of Rapid HIV Testing in Conjunction with a World Wide Web Enabled Expert System for Managing Occupational Postexposure Prophylaxis (PEP).
  Authored by Bindu Vazirani, Philip Mathew, Yen-Hong Kuo, and Joseph F. John.

• 324. Comorbidity and Clinical Indicators in a Cohort of 335 HIV1 Patients 1996-1999.
  Authored by M. Keith Rawlings, Christina De Guzman, Ralph Slaker, Elizabeth Hamel, and Diane Lapins.

• 329. Efficacy of Amprenavir-Containing HAART Regimens in Protease Inhibitor-Experienced Patients.
  Authored by Stephen L. Becker, Anthony J. Scarsella, Jeffrey D. Chulay, Gregory P. Fusco, and Neil M. Graham.

• 330. Amprenavir Inhibitory Ratio and Virological Response in PI Experienced Patients Receiving Amprenavir-Efavirenz Containing HAART Without or With Ritonavir.
  Authored by Xavier Duval, Claire Lamotte, Esther Race, Gilles Peytavin, Florence Damond, Diane Descamps, Francois Clavel, Catherine Leport, and Jean Louis Vilde.

• 331. Abacavir 1 Combivir? Given Under Directly Observed Therapy (DOT) is a Potent HAART Regimen.
  Authored by Larry Kirkland, Margaret Fischl, Karen Tashima, David Paar, Thomas Gensler, Neil M. Graham, Haitao Gao, Jaime Hernandez, and Siegrid Hessenthaler.

• 333. Retrospective Case-Control Study of the Impact of Hydroxyurea on the Toxicity, Virologic and Immunologic Responses to HAART Therapy in HIV-Infected Patients.
  Authored by Omar Y. Gonzalez, John Jovanovich, Douglas Mayers, and Scott Kaatz.

• 336. Trough Plasma Levels of Nelfinavir or Indinavir Correlate with Virological Response to HAART in HIV Infected Patients.
  Authored by Xavier Duval, Gilles Peytavin, Isabelle Albert, Jean Luc Ecobichon, Vincent Le Moing, Pascale Longuet, Olivier Adam, Franc, Oise Brun-Vezinet, France Mentre, Catherine Leport, and Jean Louis Vilde.

• 338. Nevirapine (NVP) Plus Efavirenz (EFV)-Based Salvage Therapy in Heavily Pretreated HIV-Infected Patients.
  Authored by Joseph Olivieri.

• 341. Reduction in HIV Viral Load after Short Term Monotherapy with DAPD.
  Authored by Melanie Thompson, Harold A. Kessler, Joseph Eron, Steven Deeks, Roberto C. Arduino, Jeffrey Jacobson, Nirupama Sista, Joseph Quinn, Cypryan Klish, Joseph Bigley, and Franck Rousseau.

• 352. Increasing Incidence of Nucleoside Analog-Associated Steatohepatitis and Lactic Acidosis in Obese HIV-Infected Patients.
  Authored by Manuel P. Revuelta.

• 353. Factors Influencing Fat Distribution in HIV-associated Adipose Redistribution Syndrome (HARS).
  Authored by Julian Falutz, Marshall Glesby, Ross D Pettit, Michael Kleintop, John Balser, Donald P Kotler, and Norma Muurahainen

• 358. Adherence with Antiretroviral Therapy: A Comparison of Self-Reported Adherence with Pharmacy Records.
  Authored by William J. Burman, Larry Sharkey, Sampson James, James Joyner, Patty Hamilton, and Jeff Rosky.

• 364. Utility of a Genotypic Assay in HIV-1 Infected Patients Failing Salvage Therapy.
  Authored by Sheila M. Badri, Kimberly Y. Smith, Diana D. Huang, T. Giesler, J. Bremmer, C. Brown, Harold A. Kessler, and Beverly E. Sha.

• 365. Poor Response to Therapeutic Regimen Changes Following Viral Genotyping in Children Infected with HIV.
  Authored by Nicole J. Cohen, Christine Elsen, Sophia Taylor, and Janet A. Englund.

• 377. Lactic Acidosis in Hospitalized HIV-Infected Patients Treated with Nucleoside Reverse Transcriptase Inhibitors.
  Authored by Michael E. Coghlan, Jean-Pierre Sommadossi, Wickliffe J. Many, Michael S. Saag, and Victoria A. Johnson.