20 Years After AIDS Emerges
HIV's Complexities Still Loom Large
Joan Stephenson, PhD from the NY TIMES
As the HIV/AIDS epidemic approaches the 20th anniversary of the first mysterious reports of people with the syndrome, researchers and clinicians continue to grapple with the complexities of the virus.
Those complexities were readily evident here at the 8th Annual Retrovirus Conference, where some 3000 participants gathered to hear reports of the latest findings.
Although at least 15 drugs have been approved to treat HIV infection and experimental therapies are in the developmental pipeline, new reports of rising resistance rates as well as a better appreciation of potential adverse effects underscore the urgent need for new antiretroviral agents. At the same time, discoveries about the molecular underpinnings of HIV and the genetic makeup of people infected with the virus are providing fresh insights into variations in risk for complications involving anti-HIV drugs and for disease associated with HCV co-infection.
Although drug-resistant HIV has been an important concern almost since the first anti-HIV drugs became available, the problem was primarily the result of HIV evolving in patients in response to the selection pressure posed by the drug regimen. Now, however, researchers have learned that the proportion of new infections caused by strains of the virus that are already resistant to one or more antiretroviral drugs has sharply increased a development that has sobering implications for treatment efforts.
In one study, which grew out of a program to detect people recently infected with HIV in several cities in the United States and Canada, investigators had identified 394 individuals between 1995 and last May, all of whom were diagnosed within 3 months of infection. None of the study participants had ever taken any anti-HIV drugs.
Testing for HIV resistance revealed that one in seven patients (14%) infected during 1999 and 2000 had HIV strains showing a tenfold reduction in susceptibility to at least one class of antiretroviral drugs, noted Susan Little, MD, of the University of California, San Diego, School of Medicine, who presented the group's findings. Only 3.5% of patients infected in 1995 through 1998 acquired an HIV strain with a comparable level of resistance.
In addition, 5.8% of patients infected in 1999 and 2000 acquired HIV strains that were resistant to two classes of anti-HIV drugs compared with 0.4% of patients infected during the earlier period.
Such patients "are less likely to suppress virus replication with therapy, take longer to suppress the virus, and have a shorter time to therapy failure," said Little. The result: a narrowing of the range of therapeutic options available for potential use in the patient's continuing battle with HIV.
Another report, from France, on resistance rates among newly infected individuals demonstrates that the spread of drug-resistant HIV strains is not just a North American phenomenon. In a retrospective study of 121 newly infected patients, resistance testing revealed that in 1999, 12 (10%) had mutant HIV strains associated with resistance to at least one class of antiretroviral drugs, said Marie-Laure Chaix, MD, of Hôpital Necker, in Paris.
Why is the frequency of drug-resistant virus increasing, at least in the United States? (The prevalence rate of drug-resistant HIV in France was already 9% in 1996, compared with 10% in 1999.) In recent years, increasing numbers of patients have been receiving potent combinations of anti-HIV drugs earlier in the course of their infection, said Little. That means there are more patients who develop resistance to therapy and who can transmit resistant virus to others.
The new findings have important implications for clinical management of patients with HIV infection. Treatment guidelines issued last year by a panel from the International AIDS Society–USA suggested that physicians consider routine susceptibility testing before initiating therapy in acute HIV infection (but not delaying treatment for results) and in treatment-naive patients with established infection, especially in regions having higher levels of primary drug resistance.
Studies suggest that a drug-resistant strain of HIV gradually reverts back to the nonresistant wild type when a patient is no longer taking the drug in question. However, resistant mutants can quickly emerge if the patient resumes taking the drug again. Knowing that a patient has a reservoir of such mutant virus in his or her body may help clinicians tailor therapeutic regimens to avoid use of drugs to which the virus is already resistant.
NOVEL ANTI-HIV AGENTS
With drug resistance undermining the effectiveness of available antiretroviral drugs, AIDS clinicians are looking toward experimental antiretroviral agents to expand treatment options.
Furthest along in the research pipeline are fusion inhibitors, which work by preventing HIV from attaching to and entering host cells. Because fusion and other entry inhibitors target a different phase of HIV's life cycle than currently available antiretroviral drugs, researchers predict that the experimental drugs could be particularly valuable for patients who are infected with HIV strains resistant to standard therapies.
In a phase 1/phase 2 study of one experimental fusion inhibitor, T-1249 (in development by Trimeris Inc, Durham, NC), 63 HIV-infected patients received once- or twice-daily injections of various doses of the drug for 14 days. The drug substantially lowered the patients' viral load and, for the most part, was well tolerated, reported Joseph Eron, MD, of the University of North Carolina at Chapel Hill School of Medicine.
Other investigators are attempting to thwart drug-resistant HIV by developing new versions of currently used antiretroviral drugs with a major twistan ability to foil the emergence of resistant HIV strains, said John Erickson, PhD, of Tibotec, a Mechelen, Belgium–based company with branches in Ireland and the United States. Erickson and Rudi Pauwels, PhD, one of Tibotec's cofounders, described a new family of "resistance-repellent" experimental agents.
The new agents bind very tightly to the targeted sites of HIV, which allows them to inhibit the activity of enzymes such as protease or reverse transcriptase that are needed for HIV replication. While antiretroviral drugs generally lose their effectiveness when a viral mutation alters the site where the drug binds to the virus, a resistance-repellent agent is flexible enough to maintain its grip on the binding site even in the presence of viral mutations that change the binding site's shape, explained Erickson.
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) currently in use have potent activity against HIV, but the extensive cross-resistance seen in this class of drugs means that using new NNRTIs with activity against resistant virus subsequently decreases the range of treatment options available for patients. Pauwels reported here that in a 7-day phase 1/phase 2 placebo-controlled trial of a resistance-repellent NNRTI, TMC120, in 43 HIV-infected, drug-naive patients, the experimental agent reduced HIV plasma levels as much as 100-fold without producing significant adverse effects.
In vitro studies have demonstrated that TMC120 is a potent inhibitor of HIV strains that are resistant to currently used NNRTIs. Phase 2 testing of the agent in NNRTI-naive and -experienced patients is under way.
In addition, laboratory studies testing a prototype drug, TMC126, against a panel of HIV mutant strains known to be resistant to protease inhibitors showed that the agent "had an extraordinary ability to block viral replication in vitro across a broad spectrum of multidrug-resistant HIV strains," said Erickson. "It also blocks the emergence of resistance in laboratory experiments along known pathways."
The experimental agent is a "very, very powerful protease inhibitor that could suppress drug-resistant virus," noted David Ho, MD, of the Aaron Diamond AIDS Research Center in New York City. "I think that's pretty impressive."
But the proof of TMC126's utility and safety awaits clinical trials. Studies in cell cultures and animals and preliminary findings from a phase 1 safety study in Europe have not uncovered any toxicity problems, so investigators are hopeful that this agent and others like it might be useful as salvage therapy for patients with drug-resistant HIV or as initial therapy to help prevent development of resistance.
While some researchers are investigating drug-virus interactions at the molecular level, others are zeroing in on genetic differences between people and exploring how such differences affect complications associated with treatment for HIV infection and risk for disease associated with HCV coinfection.
For example, researchers from the University of Basel in Switzerland and researchers from the Swiss HIV Cohort Study are looking for genetic smoking guns that help explain why 70% of patients treated with protease inhibitors experience a substantial increase in blood cholesterol levels, while the other 30% do not.
The investigators found that a single nucleotide variation in a gene called SREBP-1c (sterol regulatory element binding protein 1c) that plays a role in cholesterol and triglyceride metabolism causes people who carry the gene to be prone to this adverse effect when they take protease inhibitors, said André R. Miserez, MD. About 70% of people have one or two copies of this genetic variant; those with a single copy of the polymorphism have a mild elevation in cholesterol levels, while those with two copies are more severely affected.
It's a simple matter to detect this gene variant in patients, said Miserez. That means that for the first time, it may be possible to predict who will be at risk for this adverse effect and treat them aggressively with cholesterol-lowering drugs.
Investigators also unveiled new findings about the effects of a particular gene mutation on people who are coinfected with HIV and hepatitis C virus (HCV). Previously, studies had revealed that this mutation a deletion in a receptor molecule called CCR5 that HIV uses to enter a cell (CCR5- 32) was associated with protecting some people against HIV-1 infection and disease progression. But while having the CCR5-32 variant may have a salutary effect against HIV-1 in people who are homozygous for this mutation, having a double dose of the mutation appears to be a handicap for people infected with HCV, said Rainer P. Woitas, MD, of the University of Bonn, Germany.
Woitas and his colleagues found in a study of 153 individuals infected with HCV, 102 infected with HIV, 130 infected with both viruses, and 102 controls (blood donors with no known infections) that CCR5- 32 was present in people with HCV three times more often than expected. In addition, patients with two genes having the mutation had significantly higher levels of HCV in their blood than those with the normal form of the gene.
"This suggests unfavorable effects of this mutation for the course of HCV," said Woitas.
In the United States, HIV and HCV coinfection is fairly common due to shared routes of transmission, especially injection drug use, and the German group's discovery about the CCR5- 32 mutation has treatment implications for patients who are infected with both viruses. Researchers are working to develop "entry inhibitors" intended to block HIV's use of the CCR5- 32 receptor to gain entry to host cells.
If they succeed, the entry inhibitors targeting CCR5- 32 would be a welcome addition to the antiretroviral armamentarium but might be off-limits for people coinfected with HIV and HCV. Such drugs "would likely only exacerbate the hepatitis C infection," Woitas said.