20 Years of HIV Science: Setbacks and Activism
2nd International AIDS Society Conference on HIV Pathogenesis and Treatment
It was billed as a scientific gathering intended to "provide new insights into HIV disease that can lead to new research directions, help speed translational research and move advances into clinical practice." But in retrospect, the 2nd IAS Conference on HIV Pathogenesis and Treatment, held July 12-16, 2003, in Paris, said as much about the convergence of social and political concerns regarding the global HIV/AIDS pandemic as it did about the science.
Approximately 6,000 delegates from 120 countries filled the auditoriums, meeting rooms, and exhibit halls of Paris's Palais des Congrès, where they shared insights into the molecular biology of HIV, clinical data on current and emerging antiretroviral therapies, the epidemiology of HIV infection and HIV disease, and strategies for providing optimum care in parts of the world where resources are severely limited.
Organizers framed this second annual IAS Conference to highlight HIV science two decades into the AIDS pandemic. Thus, the clinical and scientific sessions at the heart of the IAS Conference provided a snapshot of HIV/AIDS research and treatment two decades on. The sessions highlighted the continuing advancement and refinement of antiretroviral therapy, but also the continued resilience of HIV and growing concerns about containment, as evidenced by reports of the increasing prevalence of newly acquired antiretroviral drug-resistant HIV infections.
Three recently approved antiretroviral agents, including a new protease inhibitor (PI), a new nucleoside reverse transcriptase inhibitor (NRTI), and the first agent in a new class of drugs (fusion inhibitors), received a great deal of attention in clinical sessions at the IAS Conference.
Summaries of the presentations regarding these drugs are presented below in alphabetical order by generic name. These drugs are also discussed later in this article in sections focusing on salvage therapy and industry-sponsored satellite symposia.
Atazanavir (ATV), a once-daily azapeptide PI that received US Food and Drug Administration (FDA) approval just a few days before the IAS Conference's opening ceremony, was the focus of numerous talks in clinical presentation and industry sponsored-symposia.
In a late-breaking oral presentation, Joseph G. Jemsek (Jemsek Clinic, Huntersville, North Carolina) reported data from the metabolic substudy of the BMS-034 trial, which compared ATV 400 mg once daily (QD) with efavirenz (EFV) 600 mg QD, each in combination with fixed dose zidovudine (ZDV) and lamivudine (3TC) twice daily (BID). The metabolic substudy looked at adipose tissue changes and metabolic parameter changes from baseline to 48 weeks. The researchers found that ATV and EFV produced comparable and proportional effects on body fat distribution at week 48. They also determined that the pattern of fat increase seen in patients was consistent with normal weight gain and not with patterns of central adiposity. In addition, whereas therapy with EFV raised total cholesterol, fasting LDL, HDL, and fasting triglycerides, ATV resulted in an 11 percent increase in HDL, but a 6 percent decrease in fasting triglycerides, and was essentially neutral in its effects on total cholesterol and fasting LDL.
Atazanavir's reputation was further enhanced by a study indicating that the lipid benefits can be seen in antiretroviral-experienced patients who are switched to ATV-containing regimens. That conclusion was reported in a late-breaking poster session. Kenneth Lichtenstein et al. (University of Colorado Health Sciences Center, Denver) evaluated serum lipid levels of patients in antiretroviral failure who were then switched to regimens containing ATV or lopinavir (LPV) boosted with ritonavir (RTV) -- lopinavir/ritonavir (LPV/r). They looked at two open-label studies, one comparing ATV 400 mg QD to LPV/r BID plus two NRTIs, and the other comparing RTV-boosted ATV, ATV plus saquinavir (SQV) 1,200 mg QD and LPV/r BID each combined with tenofovir (TDF) and one NRTI. In the first study, they found that at 24 weeks, ATV lowered total cholesterol, fasting LDL and triglycerides by 2 percent, 6 percent and 2 percent from baseline, respectively. In contrast, LPV/r raised all three values 17 percent, 5 percent, and 55 percent, respectively.
In the second of the two studies looked at by Lichtenstein et al., both ATV combinations result in modest lowering of all lipid parameters, whereas LPV/r was associated with a slight rise in total cholesterol, and a 31 percent jump in triglycerides, although fasting LDL was slightly decreased among LPV/r users in this study. The researchers concluded that: "in patients who have experienced virologic failure on other PI-containing [highly active antiretroviral therapy] HAART regimens, a switch to a HAART regimen containing ATV is associated with significantly greater improvements in lipid levels compared to a switch to a HAART regimen containing LPV/r."
Emtricitabine (FTC), a new once-daily NRTI, showed promise in several studies. One such trial was the ALIZE-ANRS 99 study, a 48-week randomized prospective trial comparing FTC, didanosine (ddI), and EFV QD to a continued PI-based regimen in patients with undetectable HIV RNA plasma levels. The study researchers, led by Jean-Michel Molina (Hôpital Saint-Louis, Paris), found that the substitution of the once-daily combination maintained full control of HIV levels in plasma and was well tolerated.
In a second study, a double blind multicenter comparison of FTC QD to stavudine (d4T) BID in treatment-naive HIV-infected patients, lead author Francois Raffi (CHU de Nantes, France) reported that once-daily FTC produced a higher rate of virologic success at 48 weeks (80 percent versus 62 percent for d4T), and that FTC continued to show "durable and superior virologic efficacy and tolerability" out to 60 weeks of follow-up.
Emtricitabine was also evaluated for its efficacy in patients with HIV and hepatitis B virus (HBV) co-infections. Raffi et al. conducted three multicenter, 48-week studies to assess the following triple-drug regimens:
They found that "FTC as a component of HAART produced potent suppression of HBV DNA in co-infected patients with HIV RNA suppression."
South African researchers also found that FTC provided significant efficacy when included in an antiretroviral regimen given to treatment-naive patients with high pre-treatment viral loads (>100,000 copies/ml).
Enfuvirtide, also known as T-20, generated a considerable amount of buzz as the first agent in the new class of therapies known as fusion inhibitors. This agent has a novel mechanism of action, blocking gp41-mediated fusion of HIV-1 to host cells.
In an analysis of virological response of T-20 in the TORO 1 and TORO 2 trials, Julio Montaner (University of British Columbia, Vancouver) said that the virologic response to T-20 plus optimized background (OB) therapy is directly related to the activity of the background regimen itself.
A different analysis of the TORO 1 and TORO 2 data by researchers from Stanford University and Roche Pharmaceuticals found the combination of T-20 and an OB regimen increased the time to virological failure and the mean change in HIV-1 viral load and CD4 cell counts compared to the background regimen alone. Enfuvirtide administered to the patients with genotypic sensitivity scores of 1 to 2 or 3 to 4 provides a greater than 2.3-fold predicted benefit in mean overall survival compared with those with GSS scores of 0. When given to patients with baseline CD4 cell counts >100 cells/mm3, T-20 was predicted to result in increased mean overall survival of 2.4 years, compared with 0.9 years when given to patients with CD4 counts <100 cells/mm3. The researchers found that "the clinical prognosis was more favorable with [T-20] plus OB than with OB alone ... [T-20] is expected to provide greater benefit in prognosis among patients in the higher [baseline] CD4 subgroup and those with remaining active antiretroviral therapy options (higher GSS)."
Triple-NRTI therapy suffered some cruel blows, but other drugs fared considerably better in one of several scientific sessions on antiretroviral therapy.
In a 24-week study of an NRTI-sparing regimen combining RTV-boosted LPV and EFV, researchers from the BIKS study reported that the combination reduced HIV RNA levels to <50 copies/mL in 76 percent of treated patients. Virologic success (<400 copies/mL) was achieved in 67 of 72 patients treated (93 percent). The combination of LPV/r and EFV showed a similar efficacy to classic NRTI-based regimens with "acceptable" tolerance. Most dropouts from the study for safety occurred in the early weeks of the study, and there was only one virologic failure.
In a study comparing an NRTI-sparing regimen of indinavir (IDV), RTV, and EFV with the same three drugs plus an NRTI (d4T), Michael Stek Jr. (Merck & Co.) reported that at 48 weeks the NRTI-sparing regimen was similar in both safety and efficacy to the NRTI-containing regimen.
But in a presentation that raised some eyebrows among conference delegates, Roy M. Gulick (Weill Medical College, Cornell University, New York) reported on results of the ACTG 5095 trial, comparing three PI-sparing antiretroviral regimens for the initial treatment of HIV. The trial compared Trizivir (ZDV/3TC/ABC) with Combivir (ZDV/3TC) plus EFV and with Trizivir plus EFV in more than 1,100 patients. The study was halted early due to the fact that the rates and time to failure among patients on the triple-NRTI arm was "demonstrably inferior to each of the two EFV-containing regimens," Gulick said. Patients in the triple-NRTI arm were offered the chance to continue in the study with either of the two EFV-containing regimens.
In another study presented later in the same session, a triple-NRTI combination of ABC, 3TC, plus TDF also failed to make the grade, according to Charles Farthing (AIDS Healthcare Foundation, Los Angeles). He reported that of 19 patients in the study, 11 (58 percent) had virologic failures, and only five had a virologic response. "These preliminary results raise concerns about potency and efficacy of the once-daily combination in naive patients. Until further data are available, this regimen, especially once-daily, should be avoided," Farthing concluded.
Martin Markowitz (Aaron Diamond AIDS Research Center, New York) reported that a combination of Trizivir and EFV for induction in antiretroviral-naive patients treated for 48 weeks produced viral RNA of <50 copies/mL in 61 percent of patients -- 90 percent in an intent-to-treat (ITT) analysis. There was a somewhat high dropout rate due to adverse events, however, with about 30 percent of patients quitting. Nonetheless, Markowitz said, the combination of Trizivir and EFV is a "compact and potent regimen that can effectively reduce viral RNA in patients with broad ranges of viral RNA and CD4 cell counts."
New drugs in existing therapeutic classes and emerging drugs in new categories offer promise in the treatment of patients with multi-drug-resistant HIV infection or advanced, late-stage infection, according to speakers at a forum on salvage therapy regimens.
Each stage of virologic failure may require a different intervention strategy, said Schlomo Staszewski (J.W. Goethe University, Frankfurt am Main, Germany):
Robert L. Murphy (Northwestern University Medical School, Chicago) briefly discussed new and emerging antiretroviral agents as salvage therapy options, including T-20, ATV, and FTC.
"Atazanavir was developed for initial therapy but with a little RTV boosting it looks like it's highly effective for salvage therapy as well," Murphy said. He pointed to ATV's potency, once-daily dosing, unique resistance profile, and good lipid profile versus a standard PI regimen (RTV-boosted LPV). He also touched on new drugs in development, including DPC 817 (an NNRTI), and T-1249 (a fusion inhibitor that is a follow-up to T-20). One old drug -- MIV-310 (FLT) a thymidine analog that was abandoned due to toxicity -- is being looked at in lower doses in new studies, which suggest that it may be effective in treating multi-drug resistant strains, at least in vitro, Murphy said.
Among emerging drug classes, Murphy mentioned integrase inhibitors, d-amino acid peptides, and TAT-TAR antagonists.
In a study comparing unboosted ATV with LPV/r in combination with two NRTIs in PI-experienced patients in virological failure, Calvin Cohen (Community Research Initiative of New England, Boston) reported that there were "robust increases" in CD4 cell counts and significant declines in HIV RNA in both treatment groups. Although the non-boosted ATV showed slightly less antiviral efficacy than LPV/r, ATV had a significantly more favorable lipid profile. He said that ATV might be a good therapeutic option for antiretroviral-experienced patients in whom lipid management is a priority. In a discussion at the end of the forum, he also suggested that boosting ATV with 100 mg RTV could make ATV-based regimens even more effective.
That last conclusion seems to have been borne out by a study pitting ATV/r or ATV in combination with SQV against LPV/r in combination with TDF, reported by Bonaventura Clotet (Retrovirology Laboratory and HIV Unit, Hospital Universitari Germans Trias I Pujol, Barcelona). In an interim analysis of the BMS AI424-045 study, the researchers found that the ATV/r regimen was comparable to LPV/r at viral load reduction. In contrast, the ATV-SQV combination was less effective than either of the two boosted regimens. ATV with either RTV or SQV was safe and well tolerated, and had a better lipid profile than LPV/r. ATV was associated with elevated bilirubin levels and a small number of cases of clinical jaundice, but these were not serious and did not lead to patient dropout. The LPV/r combination was associated with more frequent diarrhea.
The session also contained results of a subgroup analysis of the CPCRA 064 trial, which examined whether structured treatment interruption could benefit patients with advanced treatment failure. The analysis confirmed earlier results suggesting that treatment interruption does not confer any immunological or virological benefit, said Jody Lawrence (University of California, San Francisco).
In a satellite symposium sponsored by Bristol-Myers Squibb, which markets several anti-HIV agents (specifically ATV, EFV, d4T, and ddI), Giovanni di Peri (University of Torino, Turin, Italy) said that ATV is attractive as an antiretroviral because of its once-daily dosing, low pill burden, lack of cross resistance in PI-naive patients, and favorable lipid profile. The availability of a once-daily PI may help to address non-compliance issues centered on regimen complexity and high pill burden.
Noting that patients must take 90 to 95 percent of their prescribed antiretroviral doses daily to optimize virologic suppression, di Peri suggested that anything that can be done to reduce pill burden and simplify dosing regimens would likely enhance compliance.
Kathleen Squires (University of Southern California, Los Angeles) described the use of ATV in PI-naive patients, noting that the drug appears to be lipid neutral: "There is no negative impact in important metabolic parameters, including cholesterol, triglycerides, insulin, and glucose," according to Squires. In a study comparing ATV with EFV, both in combination with ZDV and 3TC, the drugs were comparably effective and had similar lipid profiles. ATV was generally safe and well tolerated, with adverse events similar to those seen with EFV.
A similar experience was seen by Clotet, who reported that in a study of ATV in treatment-experienced patients who had failed at least two antiretroviral regimens (BMS-045), RTV-boosted ATV was comparably effective to RTV-boosted LPV, with undetectable viral loads (<400 copies/mL) occurring in 64 percent and 62 percent of patients, respectively. Both regimens were well tolerated, although diarrhea occurred three times more frequently with LPV/r than with ATV/r.
"What do we need a new PI for, anyway?" asked Cohen, tongue in cheek. He said that ATV "addresses and improves on several issues we're seeing in the current standard of care." The drug has established efficacy, a favorable lipid profile (in which lipid decreases are significant and sustained at more than two years), and a distinct resistance profile. Cohen noted that in treatment-naive patients resistance is infrequent, and when it does occur, it has always been the 150L mutation, which does not confer cross-resistance to other PIs and has been associated with increased in vitro sensitivity to other PIs.
Cohen said that ATV has similar efficacy to standard-of-care regimens containing EFV in treatment-naive patients, as demonstrated by similar mean declines in baseline HIV RNA levels at 48 weeks. In addition, ATV-containing regimens were associated with significantly greater increases in CD4 cell counts, he said. ATV-based therapy also maintained or improved virologic response in treatment-experienced patients switched. With RTV boosting at the 300 mg QD dosing level, ATV-based regimens were comparably efficacious to standard-of-care regimens containing LPV/r in patients with prior PI failure.
A satellite symposium sponsored by Boehringer Ingelheim, which markets nevirapine (NVP) and is developing the investigational PI tipranavir (TPV), was marked as much by an unplanned event as by the scheduled program: the session was briefly interrupted by a handful of activists from ACT UP Paris, who took the stage to demand patient access to TPV. The protestors called for immediate access to TPV for patients with severe treatment failure, and relaxation of entry criteria to a planned compassionate-use program. Acting as spokesman for Boehringer Ingelheim, Douglas Mayers of the company's international virologic therapies division, noted that TPV is in short supply, and that some of the drug was pulled from pivotal clinical trials in order to ensure adequate amounts for the compassionate-use program.
The clinical portion of the program focused on adverse events and new insights into therapy.
Although anti-HIV therapy is likely to result in an excess risk of coronary heart disease (CHD), the benefits of antiretroviral therapy clearly outweigh any possible risk, according to Jens D. Lundgren (Hvidovre University Hospital, Copenhagen). He noted, however, that most evidence to date for possible cardiovascular effects of antiretroviral therapies come from cohort studies, which by definition cannot define causality. Lundgren recommended cardiovascular risk assessment for all patients on antiretroviral therapy, both as a means of identifying those at risk and as a teaching tool. He said that a reasonable strategy for medical intervention might be when an individual's 10-year risk for CHD is greater than 10 percent. Interventions may include diet, exercise, and smoking cessation.
Joep MA Lange, representing the International Antiviral Therapy Evaluation Center (IATEC), reported on a study comparing antiretroviral regimens based on either NVP (QD or BID) or EFV or a combination (the 2NN study). The study showed that the dual NNRTI regimen was significantly less effective than either of the single NNRTI regimens, primarily due to toxicity-related dropouts. The study found that antiretroviral regimens based on either NVP or EFV had comparable immunological and virological efficacy. In terms of safety, there was a trend toward more liver enzyme elevation and skin rashes in NVP-treated patients, with EFV accounting for significantly more psychiatric and central nervous system (CNS) adverse events. Lange said that co-administration of NVP and EFV is not recommended due to safety concerns.
Changes in serum lipid profiles associated with PI-based antiretroviral regimens are greater than can be explained by the "return-to-normal" phenomenon associated with effective HIV suppression, according to Mark van der Valk (University of Amsterdam, The Netherlands). NNRTI-based regimens, in contrast, are associated with significant rises in HDL, and smaller increases in LDL and triglcyerides, van der Valk said. He suggested that although antiviral efficacy is the primary concern, it might be appropriate to initiate or switch to NNRTI-based regimens in the treatment of patients with pre-existing cardiovascular risk factors.
Hepatotoxicity of antiretroviral regimens is a serious issue, but it may be confounded by issues such as co-infection with hepatitis B or C, use of other drugs, alcohol, or even over-the-counter herbal preparations, said Marion Peters (University of California, San Francisco). Peters said the majority of hepatotoxicity cases are mild and asymptomatic. "HIV patients have other reasons for abnormal liver tests," Peters said.
The session was concluded by Daniel R. Kuritzkes (Harvard Medical School and Brigham and Women's Hospital, Boston), who discussed current experience with RTV-boosted TPV. The drug is a non-peptide inhibitor of HIV-1 protease that has shown activity against viral isolates resistant to currently approved PI. In preliminary studies of patients failing a first PI, TPV/r achieved a median reduction in viral load comparable to RTV-boosted SQV. More recently, the BI 1182.52 study looked at TPV/r in three dose combinations in patients infected with multiple PI-resistant HIV. At two weeks, median change in viral load was -0.9 log10 copies/mL for a dose of TPV 500 mg plus RTV 100 mg; -1.0 log10 copies/mL for a 500 mg/200 mg dose; and -1.2 log10 copies/mL for a 750 mg/200 mg dose. Grade 3 or 4 adverse events trended toward more frequent with the higher dose ranges, and there was substantial loss of virologic response in patients with three or more mutations. Based on the results, Phase III trials using the TPV 500 mg plus RTV 200 mg dose are currently underway.
Choosing antiretroviral agents for initial therapy based on the assumption of ultimate failure may be a mistake, because long-term suppression of HIV without significant drug resistance is an attainable goal, according to Joel E. Gallant (Johns Hopkins University School of Medicine, Baltimore), speaking at this Abbot Laboratories-sponsored satellite symposium. Abbott Laboratories markets RTV and LPV.
With the advent of more potent antiretroviral therapy, the focus is turning from management of inevitable resistance to selection of therapeutic regimens that prevent failure in the first place, Gallant said. Although cross-trial comparisons are fraught with difficulties, a meta-analysis comparing antiretroviral trials suggested that newer regimens using more potent agents in more convenient and tolerable regimens can result in a greater number of participants achieving virologic suppression compared with earlier trials, Gallant noted.
Gallant said that the pendulum is swinging back toward the concept of "hit early and hit hard" to achieve maximum viral suppression at the earliest opportunity. He cited results from Study 720 of LPV/r indicating that a high percentage of patients had undetectable viral loads at four years. In a second trial (Study 863), there were no primary or active site mutations in HIV among 51 patients with a known genotype who received RTV-boosted LPV for up to 96 weeks; in contrast, 44 of 96 patients (46 percent) of those receiving nelfinavir (NLF) had mutations.
Kuritzkes discussed the concept of "viral fitness" -- the ability of a virus to replicate in a given environment, which is distinct from -- but interrelated with -- viral replication capacity and virulence. The overall potency of a regimen is important for determining rates of resistance, he explained, but it appears the combination of a genetic barrier to high-level resistance seen with PIs and the pharmacologic barriers thrown up by RTV boosting make patients on RTV-boosted PI regimens less likely to fail therapy than those on other antiretroviral regimens.
Keeping patients on antiretroviral regimens after they begin to experience significant side effects is a major challenge to continued success, said José R. Arribas (La Paz Hospital, Madrid). Arribas emphasized that survival benefits of antiretroviral therapy outweigh the modest increase in cardiovascular risk seen in some studies.
When it comes to antiretroviral therapy, more drugs may not necessarily be better, noted Mark Nelson (Chelsea and Westminster Hospital, London). He pointed to the so-called Treasure Coast cohort of 15 patients, 11 with prior PI exposure, who were switched to monotherapy with LPV/r because of either toxicity or virologic failure. Of this cohort, 12 patients had a viral load of less than 400 copies/mL, and nine of the 12 achieved a viral load of <50 copies/mL with a median of 34 weeks therapy.
Among the most important clinical news stories to come out of the meeting was the release of data from the CATCH (Combined Analysis of resistance Transmission over time of Chronically and acute infected HIV patients in Europe) study.
The CATCH study looked at reverse transcriptase (RT) and protease sequence information from 1,633 newly diagnosed, recently and chronically infected patients from 17 European countries. The researchers looked at the prevalence of resistance from 1997 to 2002.
The researchers found that prevalence of primary drug resistance among people in Europe who are newly diagnosed with HIV is about 10 percent. The prevalence of resistance among infections with viral subtype B -- the type most prevalent in Europe during the study period of 1996 to 2002 -- was about four times higher than in non-B subtypes, which are more commonly found in Africa, noted David van de Vijver (University Medical Center Utrecht, The Netherlands), who presented the study. Transmission of drug-resistant non-type-B strains in Europe is also occurring, he noted.
Speaking at a press briefing before the session, Lange said that the study shows that when it comes to new infections with drug-resistant HIV strains, "we're never going to be able to prevent it from happening." Lange went on to say that, "the idea that we should not give HAART to people in developing countries to prevent the emergence of resistance is ridiculous. Nobody is asking us to stop giving drugs to patients in the United States and Europe."
Overall, the researchers found that the following prevalence of any major resistance-related mutation during the study period was 11.6 percent. Resistance to at least one NRTI was 9.2 percent, while infections resistant to any NNRTI was 2.7 percent. Resistance to a PI was detected in 2.3 percent of all infections, and resistance to at least two antiretroviral drug classes was 1.8 percent.
The CATCH study researchers recommend that because of the high prevalence of resistance, baseline sequencing should be considered in newly diagnosed patients who became infected in Europe.
Other presentations at the IAS Conference focused on the mechanisms of resistance. According to Kuritzkes, the prevalence of infection with HIV-1 strains that are resistant to at least two classes of drugs now exceeds 1 percent and is creeping up toward 2 percent.
Calling drug resistance "the inevitable consequence of our failure to fully suppress the virus," Kurtizkes noted that the benefits of continued drug therapy on morbidity and mortality of infection persist despite the emergence of drug resistance, and that the benefits continue until the highest levels of viral drug resistance are reached. He said that resistance testing is recommended in acute or recent HIV infections, before initiation of antiretroviral therapy in established HIV infections, following first regimen or multiple regimen failure, and in pregnancy if the mother has detectable plasma levels of HIV-1 RNA.
Boehringer Ingelheim's Mayers discussed results from the BI 1182.52 study looking at the inhibitory quotient (IQ) of RTV-boosted TPV. The IQ, which is the ratio of trough plasma concentration of a drug to the protein-adjusted viral IC50, is a good measure of the potential therapeutic margin of antiretroviral therapies. In a trial comparing three doses of TPV/r twice daily in patients with triple antiretroviral drug class experience, the IQ of TPV/r compared favorably with IQ data for other PIs given to treatment-naive patients. This finding "suggests that TPV/r may provide antiviral activity in the majority of highly treatment-experienced HIV-positive patients," he said.
In other news, researchers from the ERA trial comparing phenotypic resistance testing added to genotypic resistance versus genotypic testing alone, found that testers could probably save money by skipping the phenotypic part. The trial result showed no significant differences in terms of virologic and immunologic response between therapy guided by genotype testing alone or genotype-plus-phenotype. The researchers also found that access to phenotypic resistance testing did not significantly alter the composition of new drug regimens.
Means for coping with drug resistance and adverse events in HIV-1 were also the subject of a separate oral abstracts session on resistance and pharmacology.
Anders Malmsten (Uppsala University, Sweden) reported on a simple assay that combines viral load and phenotypic drug susceptibility testing by measuring virion-associated reverse transcriptase activity. The assay, which can detect activity down to a few thousand particles, correlates well with a standard, commercially available viral load assay, Malmsten said. He noted that the assay might be helpful for managing drug therapy in regions where healthcare resources are limited.
Such an assay could be of benefit in countries such as Cameroon, where a study monitoring the prevalence of antiretroviral-resistant HIV-1 strains in patients receiving either antiretroviral therapy or single-dose NVP to prevent mother-to-child HIV transmission found a high rate of mutations in treated patients. In an analysis of PCR-amplified samples, researchers from Hopital du Jour HCY, BP81 in Yaoundé, Cameroon, and other African colleagues found resistance mutations in 19 of 34 samples, including high-level resistance to three antiretroviral classes in some patients. They concluded that antiretroviral therapy guidelines and biological monitoring must be implemented in Africa to prevent rapid selection of resistance.
Circumstances are considerably different in France, where a study of genotypic drug resistance mutations in 2001 to 2002 showed no significant changes in frequency of resistant virus from 1996 to 2000. The researchers -- from ANRS and the PRIM, INTERPRIM, and PRIMSTOP study groups -- did find an increasing trend in the frequency of non-B subtype strains, from 19 percent in 1999 to 2000 to 24 percent in 2001 to 2002.
Another French study looked at the efficacy of an RTV-boosted amprenavir (APV) combination in PI-experienced (but APV-naive) patients in virological failure and found that treatment with APV 600 mg plus RTV 100 mg led to a median viral load decrease of -1.32 log by week 12, and -1.46 by week 24.
In a meta-analysis of published clinical trials, researchers from France and Switzerland determined that in NRTI-experienced patients with advanced infections, PI-based triple regimens appear to be superior to regimens based on the NNRTIs NVP or DLV.
In a study that spanned the globe from Switzerland, to Thailand, to Australia, researchers found that in a planned treatment interruption strategy of one week on, one week off, 19 of 36 (53 percent) of evaluable patients had two successive HIV RNA concentrations above 500 copies/mL at the end of the week off therapy, and were classified as virologic failures. This arm of the study was halted.
Better results were seen in a study of the use of antiretroviral prophylaxis to reduce the risk of HIV transmission from mother to child during breast-feeding (the SIMBA study). Joseph Vyankandondera (Centre Hospitalier de Kigali, Kigali, Rwanda) reported that in a trial of 397 infants of HIV-positive women in Uganda and Rwanda, a combination of antiretroviral prophylaxis (with either NVP or 3TC) and counseling to the mothers on breastfeeding practices kept late postnatal transmission of infection (out to six months) to 1.1 percent of infants receiving 3TC, and just 0.6 percent of those receiving NVP.
A rather different study out of the Hospital La Paz in Madrid looked at the use of ambulatory EEG and therapeutic drug monitoring of patients on EFV who experience sleep abnormalities. The researchers found a dose-related correlation, with sleep problems tending to occur at plasma drug levels of about 4 ng/l or higher. They found that dose adjustment appeared to resolve or ameliorate problems in most patients.
When it comes to mechanisms of toxicity of antiretroviral drugs, there is plenty of blame to go around, suggested researchers presenting data at an oral abstract session.
Protease inhibitors and NRTIs can exert negative effects on various organ systems, including the liver, muscle, pancreas, bone and CNS, said Jacqueline Capeau (Hôpital Ste. Antoine, Paris). She noted that lipodystrophy and metabolic changes might be linked to hepatotoxicity and alteration of glucose metabolism mechanisms. Drug effects may also be influenced by co-infection with hepatitis B virus or hepatitis C virus.
Morris Schambelan (University of California, San Francisco) discussed possible approaches to treating lipodystrophy and metabolic changes using thiazolidinediones. He cited two studies looking at the use of rosiglitazone 8 mg/day (one for 12 weeks and the other for 24 weeks), in which use of the drugs significantly resulted in improved insulin resistance profiles, decreased visceral adipose tissue, and increased subcutaneous abdominal tissue. He also briefly described pilot studies using recombinant humanized leptin to treat acquired generalized lipodystrophy. In one case, administration of leptin to a woman with a massively steatotic liver caused a loss of about 2 kg of intrahepatic fat.
In an in vitro study, Capeau et al. looked at the effects of five NRTIs on adipose cell differentiation, insulin sensitivity, and cell survival. They found that three of the NRTIs tested (ABC, ddI, and 3TC) did not modify adipose cell functions. In contrast, d4T and ZDV decreased cell lipid content and mildly increased apoptosis and ZDV also induced insulin resistance. They conclude that the thymidine analogues, but not the other NRTIs, exerted adverse effects in cultured adipocytes.
Researchers from the Laboratory for AIDS Virus Research at Weill Medical College of Cornell University in New York looked at factors that might affect bone formation or retention in people with HIV who are both treatment-naive and antiretroviral-experienced. They compared the expression and biological activity of the primary cytokine responsible for osteoclast differentiation and bone resorption, receptor activator of nuclear factor kB ligand (RANKL). They found upregulation of the cytokine, and that pharmacologic levels of RTV and SQV, which have linked to osteopenia alter RANKL activity. In contrast, IDV had no effect.
Ulrich Walker et al. (Medizinische Universitäsklinik, Freiburg, Germany) investigated whether mitochondrial DNA is depleted in the livers of people receiving NRTIs. They found that current treatment with ddI, d4T, or ddC is associated with decreased mitochondrial DNA in the liver without regard to liver cirrhosis or inflammation.
Mitochondrial toxicity was also seen in a study by researchers from Hôpital Avicenne, Université Paris-Nord, Bobigny, France, who looked at patients with long-term exposure to NRTIs. They found that chronic exposure to NRTIs produced a loss of responsiveness of capsaicin-sensitive nociceptors, suggesting that the drugs may produce alterations in small peripheral nerve fibers that may be linked to mitochondrial toxicity.
The term "fat redistribution syndrome" should be retired, because lipoatrophy and lipohypertrophy that occur in people who are HIV positive may not be directly related to one another, even when they occur simultaneously in the same person, according to researchers from the NIH-sponsored Fat Redistribution and Metabolic Change in HIV Study (FRAM). They reported findings of the fat redistribution and metabolic change portions of the study at an institutional symposium.
"Forget about 'fat redistribution,' because it ain't moving," said Charles M. van der Horst (University of North Carolina, Chapel Hill).
The FRAM study was a cross-sectional population-based study looking at lipid, metabolic, and adipose tissue changes in people who are HIV positive and in controls (HIV-negative individuals enrolled in the CARDIA study). The researchers had "no a priori assumption of what constitutes the HIV lipodystrophy syndrome," said co-principal investigator Carl Grunfeld (University of California, San Francisco). The results presented here did not include data on the effects of drug therapy; those data will be presented at a later meeting, the researchers said.
Self-reports of fat loss among both men and women in the study correlated closely with objective measures, a fact that several researchers reported to be "highly reassuring."
Among the most interesting study findings was that in HIV-positive men and women central lipohypertrophy was not associated with peripheral lipoatrophy, although peripheral and central lipoatrophy in the same individual were associated, said Michael Saag (University of Alabama, Birmingham). "There's no evidence that people who gained weight in the belly lost weight in the periphery," Saag remarked.
Among men, there was significantly greater peripheral fat loss in all body areas in those who were HIV positive versus controls. Men with HIV also reported, and exams confirmed, less central fat gain.
In an analysis of data on women enrolled in the study, the researchers found an inverse association between central lipohypertrophy and peripheral lipoatrophy. In general, women who were HIV positive experienced little overall change in body fat distribution, said Abby Shevitz (Tufts University School of Medicine, Boston).
In both men and women, HIV positivity was associated with either significant changes or trends toward decline in both LDL and HDL cholesterol, and increase in triglycerides, as well as unfavorable changes in insulin and glucose parameters, suggesting that HIV infection increases risk of cardiovascular problems, said Judith Currier (University of California, Los Angeles).
The most effective approach to treating tuberculosis co-infections in patients with HIV/AIDS in the developing world is with antiretroviral therapy, according to Peter Mugyenyi (Joint Clinical Research Centre (JCRC), Kampala, Uganda), at a session on opportunistic infections in resource-limited settings.
Mugyenyi said that the patients who present to the JCRC tend to come in with advanced, late-stage disease, noting that about half of all patients present with CD4 cell counts below 100 cells/mm3 at first admission. Tuberculosis is the leading cause of death, accounting for 40 percent of all mortality at the center, he said. Other common opportunistic infections include all the usual suspects, including toxoplasmosis, Pneumocystis carinii pneumonia (PCP), and cryptococcosis, all of which are almost uniformly fatal. He pointed out that the average life expectancy is 87 years in Japan versus 33 years in Zambia.
Mugyenyi also spoke of a cruel irony or "evil convocation" resulting from the success of Uganda's HIV-prevention efforts: there is decreased HIV prevalence, but increased incidence of both AIDS and opportunistic infections.
The good news, said Mugyenyi, is that antiretroviral therapy reduces the incidence of tuberculosis by about 80 percent in HIV-positive people, and that antiretroviral therapy is the ideal form of prophylaxis for opportunistic infections. He compared the costs of various forms of therapy for two weeks of therapy for opportunistic infections, noting that treatment of PCP and toxoplasmosis infection cost more than US$100, tuberculosis therapy costs about US$40 for the same period, but antiretroviral therapy, using generic drugs, costs only US$12.
In the same session, Kevin DeCock (US Centers for Disease Control and Prevention, Nairobi) reported that there are 8 million new cases of tuberculosis per year, and 1 million deaths. In addition, there are 11.4 million people with HIV/tuberculosis co-infection, two thirds of whom are in sub-Saharan Africa.
DeCock said that most cases of tuberculosis occur in HIV-positive patients, but are transmitted primarily from those who are HIV-negative. He agreed with Mugyenyi that antiretroviral therapy is the most effective means of tuberculosis prevention and treatment in the developing world, pointing out that it reduces the incidence of the disease by about 80 percent in HIV-positive patients, although they still remain at higher risk than those who are not infected.
He cautioned, however, against half measures, saying that "a bad tuberculosis program is worse than no program at all," and that widespread, poorly implemented antiretroviral therapy can do more harm than good.
By general consensus, the highlight of the 2nd IAS Conference on HIV Pathogenesis and Treatment was the extraordinary plenary session held on Bastille Day, July 14, 2003. The session -- which took place as tanks rumbled, bands blared, and troops paraded down the nearby Champs d'Elysee in honor of France's Fête Nationale -- was co-chaired by Robert C. Gallo and Luc Montagnier, credited as co-discoverers of HIV as the pathogenic agent underlying AIDS. Both gave brief (and uninspired) remarks regarding the past, present, and future of HIV/AIDS research and treatment.
Gallo spoke of three now-absurd notions that prevailed in the medical community in the 1970s:
He noted that in the 1970s, US medical schools closed their Departments of Microbiology, and that the then-named US Centers for Disease Control (CDC) was "threatened with reduction or closure" in the then-common belief that major infectious diseases had been relegated to the medical history books.
Later in the program, Montagnier called for efforts to ensure access to medications in the developing world, as well as more coordinated surveillance, and, it goes without saying, research into new therapies and preventive vaccines.
It was clear to all present, however, that the star attraction of the session and indeed the highlight of the conference was the speech by Nelson Mandela, a champion of human rights, freedom, and dignity, and a tireless advocate for access to critical health services for all people in all nations.
The former President of South Africa and winner of the Nobel Peace Prize in 1993, looked frail as he was helped to the podium, leaning on a cane and on the arms of aides. Yet, as he spoke, his strength and passion were as great as they have ever been.
Mandela cited United Nations estimates that:
"These numbers are staggering -- in fact incomprehensible," Mandela said. "By all accounts we are dealing with the greatest health crisis in human history. By all measures we have failed in our quest to contain and treat this scourge. And the disparity between its impact in the developed world and the developing world is a shocking reality that we cannot hide from."
Noting the devastating toll that AIDS has taken on impoverished nations, Mandela challenged the audience of scientists, clinicians, policy-makers and activists to "act for the sake of the world."
"Why have we failed? What are we going to do? In the end it boils down to one inescapable fact -- we have failed to translate our scientific progress into action where it is most needed -- in the communities of the developing world, the poorest regions of the globe. This is a global injustice [that] cannot be tolerated. It is a travesty of human rights on a global scale."
He called for dramatic expansion of prevention programs and access to treatment throughout the developing world. Noting the early promise of the Global Fund to Fight AIDS, Tuberculosis, and Malaria, Mandela mentioned the US$1 billion the United States set aside for the fund. "We would like it to be more, but we believe that this is a floor from which to start," Mandela commented. He also praised French President Jacques Chirac for committing France to a tripling of its investment in the fund, and called on the leaders of other European nations to substantially increase funding.
Mandela did not spare criticism for the leaders of nations at the center of the pandemic: "With regard to delivering effective HIV/AIDS responses on the ground, we must sadly point out that many of the countries that are most highly affected by HIV/AIDS have not done nearly enough to fight the epidemic -- especially in sub-Saharan Africa. This is completely unacceptable. It too is a travesty of human rights. Yes, these countries are poor, but we know they have the capacity to do more -- much more."
However, Mandela did single out Botswana, Senegal, and Uganda as exemplars. "These are countries that have demonstrated leadership from the very top and have made remarkable progress in both prevention and care," he said, noting that in Botswana, a relative latecomer to active intervention, more than 6,000 people are now receiving antiretroviral therapy.
He ended his remarks with an expression of "our very great concern about India, China, and Russia, which have rapidly evolving epidemics. If they follow the trends of Africa, the results will be calamitous, not only for the countries concerned, but for the whole world."
The other featured speaker at the Bastille Day plenary session was Anthony Fauci, Director of the US National Institute of Allergy and Infectious Diseases (NIAID) and a pioneer in HIV/AIDS research. In a talk illustrated with images from the medical literature and popular culture, Fauci spoke of the earliest days of the epidemic, beginning with "the realization back in the summer of 1981 that we were dealing with a new disease, as shown by [the] original Morbidity and Mortality Weekly reports from the CDC. Over the ensuing months, it became very clear that we were dealing with something much more than just handfuls of gay men in New York and in San Francisco, as the epidemiology began to unfold involving hemophiliacs, infants, [and] sexual partners of infected individuals. And, in fact, what we see now in the year 2003, is most extraordinary and in many cases and in many senses, tragic."
Fauci reviewed the rapid scientific progress in the field, including:
Challenges for the foreseeable future, Fauci said, include the development of an effective vaccine, based not solely on traditional antibody strategies, but on a combination of antibody-based and CD8-based approaches. "A safe and effective vaccine is absolutely critical and it is probably the most important and difficult scientific challenge in AIDS research," he said.
Fauci also acknowledged the role that activists played, especially in the early years of the epidemic, in advancing the cause of HIV/AIDS research and treatment. "It was activism that demanded that those who were infected with HIV, or who were at risk of infection, play a role in determining the nature of clinical trials and the access to drugs which could only be accessed through clinical trials, and it was more than a decade and a half ago that we decided to address that problem. We brought the activist to the table, and I can tell you from personal experience how the clinical trials process and the process of access is much the better for it," he said.
In remarks at the ceremony marking the official end of the IAS Conference and a parallel support conference for the Global Fund to Fight AIDS, Tuberculosis, and Malaria held July 16, 2003, France's President Chirac said that "AIDS is a powerful and crafty scourge which is shaking our societies to their core; powerfully spreading everywhere, with nothing, so far, able to stop it, craftily appearing where it is not expected and showing a remarkable ability to fight back when attacked."
Chirac, whose speech was briefly interrupted by demonstrators demanding increased funding for treatment, spoke of the devastating social and economic impacts of the HIV/AIDS pandemic, and praised the efforts of the medical communities, non-governmental organizations, and support groups who serve on the front lines of the crisis.
He called for increased coordinated global efforts to support research and treatment. "I wish, today, to issue a solemn appeal: an appeal to governments of donor countries all over the world to show more generosity, despite budgetary difficulties. This is not an act of charity; it is an act of shared responsibility in standing up to a global scourge. An appeal to the developing and transition countries to set the fight against AIDS as a national priority. An appeal to businesses, well-represented here, to do even more."
Chirac also warned against complacency: "In the developed countries the advent of multiple therapies and a certain weariness of complying with the discipline of prevention have prompted a renewed trend toward risky behavior. The critical importance of responsibility -- both collective and individual -- in dealing with this disease cannot be overstated."
Neil Osterweil is a medical writer with Osterweil & Baron Communications in Holliston, Massachusetts.
This article was provided by International Association of Physicians in AIDS Care. It is a part of the publication IAPAC Monthly.