2005 IAS in Rio de Janeiro
During the opening ceremonies on Sunday, Stephen Lewis, UN Envoy on HIV/AIDS in Africa, delivered a moving speech and a call to action. In his opening remarks, he stated, "I have spent the last four years traveling through Africa, primarily southern Africa, watching people die. I think I understand, better than most, why your collective scientific and academic work can be said to be the most important work on the planet.
"But precisely because the work you do speaks to the rescue of the human condition, you carry an immense public and international authority. I beg you never to underestimate that authority. And I beg you to use it beyond the realms of science.
"What we desperately need in the response to AIDS today are voices of advocacy: tough, unrelenting, informed. The issues are so intense, the situation is so precarious for millions of people, the virus cuts such a swath of pain and desolation, that your voices, as well as your science, must be summoned and heard."
Lewis remarked that the recent G8 Summit was a disappointment. He supports the cancellation of debt and the increase of foreign aid to 18 countries, 14 of which are in Africa. Many economies face imminent collapse due to the devastation caused by AIDS.
Additionally, Lewis called for "a major, multilateral organization to represent the needs and rights of the world's women," referring to the failure to intervene on behalf of women "the greatest single international failure in the response to HIV/AIDS."
He reminded the audience that the "proliferation of orphans has become a deluge; it's absolutely overwhelming in country after country. Governments are beside themselves: no one has any firm grip on how to handle these millions of frantic children."
He closed with an appeal to all of us to become advocates. "We can subdue this pandemic, but it will take the uncompromising voices of principle and outrage to make it happen. It will, in other words, take your voices."
Following is a brief summary of some highlights of presentations from the 3rd IAS Conference in Rio. For full conference coverage, including webcasts and transcripts of selected presentations, visit www.kaisernetwork.org/rio. See also www.ias-2005.org. -- Jeff Berry
Microbicides and Prevention TrialsA poster presented by Dean Hamer of the National Institutes of Health looked at using live microbes (a genetically engineered strain of E. coli) in vitro and in mice, that could prove to be useful in developing a durable (lasting weeks to months) and inexpensive microbicide.
Another poster supports the development of microbicides in combination for the prevention of sexual transmission of HIV-1 and other STDs. Cellulose acetate 1,2-benzenedicarboxylate (CAP), a polymer that blocks HIV-1 entry by targeting gp120 and gp41, and UC781, a tight-binding HIV-1 reverse transcriptase inhibitor (RTI), had significant synergistic and complementary effects against HIV-1.
TMC-120, a non-nucleoside reverse transcriptase inhibitor (NNRTI) which Tibotec stopped development on in 2003, is now being looked at as a promising microbicidal candidate, showing no toxicity at therapeutic levels.
One trial of 20 HIV-uninfected men measured the acceptable volume of a placebo microbicidal gel during receptive anal intercourse (RAI), and found that 15 out of 18 would use 35 ml of a microbicidal gel during RAI. Two individuals were lost to follow-up during the study.
In the "Believe it or Not" category, male genital tissue obtained by consent from gender reassignment and "other" surgical procedures, was used to develop a model that could help characterize the mechanisms of HIV-1 infection of male genital tissue and to evaluate future candidate microbicides.
Microbicides now being studied include Buffergel, Pro2000, C31G, cellulose sulfate and Carraguard -- all are in early phases and it will be some time before results are available. Ongoing prevention trials include oral acyclovir for herpes prohpylaxis (to reduce the risk of acquiring HIV); PREP (pre-exposure prophylaxis) with Viread (tenofovir) daily oral use (although some of these trials have been stopped or interrupted); and antiretroviral therapy (ART) as prevention in discordant couples. Future prevention trials will likely include microbicides containing antiretrovirals, new cervical barriers, and combinations of cervical barriers and microbicides.
Male Circumcision as Prevention?A large, randomized 21-month trial conducted by a team of researchers led by Dr. Bertran Auvert of France looked at more than 3,273 sexually active South African men aged 18-24. These were men who were uncircumcised and wishing to be circumcised. It found that adult male circumcision had a 65% protective effect against HIV.
Participants were randomized into two groups; half were circumcised and half remained uncircumcised. The number of HIV infections was three times lower in the first group than in the second (18 of the circumcised men contracted HIV, compared with 51 of the uncircumcised men). All study participants were given condoms and prevention counseling. Due to the findings the trial was stopped upon recommendation of the trial's Data Safety and Monitoring Board (DSMB), and all participants were offered circumcision.
It should be noted that the trial only looked at heterosexual men acquiring HIV from infected women through sexual transmission, and should not be applied to male-to-male, or male-to-female transmission. Further studies are needed, and additional trials are underway in Uganda and Kenya, with results expected in early 2007. And male circumcision, even if it is found to effectively reduce the risk of acquiring HIV, would be part of a larger "package of interventions" including condom usage and behavior change.
Lipodystrophy and SwitchingSeveral studies presented in Rio looked at the effects switching therapies has on lipodystrophy and lipid profiles.
In a small observational study, replacing a protease inhibitor (PI) or NNRTI with Reyataz (atazanavir) significantly reduced total triglycerides, total cholesterol and non-HDL cholesterol levels after 24 weeks. HDL cholesterol (the good one) was not significantly decreased, while viral load and T-cell count remained stable.
In a 45 patient RAVE substudy, switching from a thymidine anologue NRTI (either Retrovir or Zerit) to Viread (tenofovir) or Ziagen (abacavir) resulted in a significant improvement in facial lipoatrophy after 48 weeks. Inclusion criteria included those with moderate-to-severe lipoatrophy, no history of tenofovir or abacavir use or resistance, undetectable viral load and on stable antiretroviral therapy for greater than or equal to 24 weeks. The control group included 17 individuals who had received collagen injections. The study saw no significant differences between changes in the tenofovir and abacavir groups. Total cheek volume for all patients at week 48 was comparable to those receiving collagen injections.
Similarly, a prospective, open-label single-arm substudy, GS 903e, demonstrated that a switch from Zerit (stavudine, d4T) to Viread in those on stable initial antiretroviral therapy showed significant improvements in triglycerides, cholesterol, and LDL (the "bad" cholesterol), and a significant increase in limb fat, while some small decreases in bone mineral density were seen.
Biojector for FuzeonInjection Site Reactions (ISRs) are the most frequent reported side effect for those currently injecting Fuzeon (T-20) using a needle. A study of the Biojector injection system, a needle-free, gas-powered injection system found that after 24 weeks ISRs were significantly reduced using the Biojector, and patients reported increased ease of use with the Biojector over the standard needle. Plasma levels of Fuzeon did not differ between the needle and the Biojector. Two of the 32 patients in the study (6%) stopped due to Biojector-specific adverse events (bruising and numbness). Longer-term safety and efficacy evaluation of the Biojector for Fuzeon administration is ongoing.
"Supervirus" Loses Its SuperpowersReports of a potential unusually virulent and highly drug-resistant strain of HIV found in a New York City man earlier this year (see "Superbug or Superdud?," May/June issue) now appear to be unfounded. According to Richard Jefferys, Basic Science and Vaccine Project Director of Treatment Action Group in New York, researchers are looking at whether dual infection could be to blame. Dual infection is when a person contracts viral strains from two different people before they develop immune responses. Superinfection is when an HIV-infected individual becomes re-infected years later; superinfection and dual infection may occur in up to 10% of newly infected individuals, and both are associated with rapid progression to AIDS.
Dr. Gary Blick presented at the conference and suggested that rapid disease progression in the New York patient could be due to heavy use of crystal methamphetamine. The poster abstract refuted the concept of a new aggressive HIV strain, while suggesting host factors may best explain the rapid progression to AIDS in the New York City patient. The patient is now responding well to treatment.
Yea for EpivirEncouraging early results were followed by success in the final outcome of the E-184V study, which used Epivir (3TC, lamivudine) during treatment interruptions.
Italian researchers designed a study for patients with a failing drug regimen that included Epivir, who had Epivir resistance. Of 50 patients who requested a treatment interruption, half went off all their medications and half stopped everything but Epivir. Epivir is not only extremely well-tolerated, but it is also only associated with one HIV mutation. Therefore, Epivir monotherapy in people who already have the drug's resistance mutation is not going to lead to more drug resistance.
After a year, the Epivir group had a smaller drop in their T-cell counts, but it was not statistically significant. They did, however, have less of a drop in CD4 percentage, and this was statistically significant. So was the smaller rise in their viral loads. They also had a greater drop in viral load when everyone was put back on therapy at the end of a year.
The difference in clinical benefits was also statistically significant. The people continuing to take Epivir had less AIDS-defining illnesses. Researcher Dr. Adriano Lazzarin told Medscape.com that "patients love this solution." He said many patients weren't very comfortable going off therapy completely.
The study also found less "replicative capacity" in the people who continued to take Epivir. That is, the HIV in those people had a reduced ability to multiply.
Doctors everywhere are excited about the results of this study, which helps point to a new option for HIV management. More research is still needed. (See "The Buzz," March/April 2005.)
Kaletra OnlyThe OK study (which stands for "Only Kaletra") from Spain was s'alright. After one year on Kaletra by itself, people did just as well as those in the comparison group, who were given a more traditional, three-drug regimen. They received Kaletra with two nucleoside drugs (for example, Combivir).
Viral load and T-cell changes between the two groups were not statistically significant -- both of them did very well.
A viral load over 500 was considered a treatment failure. Of the three out of 21 patients on Kaletra only with viral load failure, all went back below 50 when two nucleosides were added to their regimen. Their viral load at the time of failure was 564; 1,270; and 3,600. One person decided to discontinue the monotherapy, and this was also considered a failure for Kaletra only.
The other good news was that none of them had a primary resistance mutation for protease inhibitors. Drug resistance, which can render treatment ineffective, is almost unheard of with Kaletra.
Watch for Kaletra Only, Plus ResistanceThen there was the report of a man in Germany who did develop resistance to Kaletra, and in turn, resistance to other drugs in its class (protease inhibitors). Still to Kaletra's credit, such reports are so rare that the authors of this report noted that this is only the third one.
The German man had been on Zerit and Epivir for years, with a low viral load. After a treatment interruption of two weeks, his viral load increased to 49,000. He had no resistance mutations to the HIV protease inhibitors and was put on Kaletra monotherapy.
At three months, his viral load had been re-suppressed to less than 50, but at 10 months, it had rebounded to 49,000. He was found to have several mutations rendering him resistant to protease inhibitors, including the L76V mutation associated with Kaletra.
It's rare, but it can happen.
Four Years With VireadViread is one of the "newest" HIV drugs on the market, so it's good to hear longer term data.
More than 90% of the 82 people starting HIV therapy for the first time still had less than 400 viral load after 192 weeks on Viread. They were also taking Epivir and Sustiva. The average change in T-cells was an increase of 391.
Some more good news: the bone mineral density loss that was seen in the first year of therapy did not progress. Only one person discontinued therapy because of an adverse event (Grade 3 amylase/Grade 4 lipase).
CCR5It's truly hopeful that there is so much interest in looking at drugs to inhibit HIV by blocking a crucial CCR5 co-receptor on the host CD4 cell. Three compounds that block CCR5 were presented in Rio and appear to be in a near dead heat race. The "viroc" class, Pfizer's Maraviroc, Schering Plough's Vicriviroc and GSK 873140, are all looking to be the next promising antiviral drug class being astonishingly similar in development, safety and antiviral activity thus far.
A data overview of five Maraviroc studies was presented that showed the drug to have a significant antiviral effect at a 300 mg dose once or twice daily. So far the drug is safe. Larger Phase II studies are currently underway.
Vicriviroc is Schering's bet for a winning CCR5 antagonist. Studies in Rio showed the drug to have similar potency (up to 1.6 log drop in viral load) as the Pfizer compound, where a smaller dose is required to achieve adequate blood levels.
GSK 873140 appears to have a very similar effect as the former drugs in very similar studies so far.
At this point in time it is difficult to see much difference other than dosages in these three co-receptor antagonists. According to monotherapy studies the drugs appear to have similar rates of half lives, or what is being referred to as "occupancy", where the agent sticks to the co-receptor for a long time after the drug is administered. Schering and Pfizer spoke of doing or planning extensive drug interaction studies, especially with some of the brand new drugs. However, Vicriviroc and GSK 873140 will move forward in clinical trials with a Norvir boost. Fasten your seat belts, the race is on.
ReversetReverset is a new drug from an older class moving forward in a larger Phase II study. The hope for this nucleoside analog is that it will work against nuke resistant virus. A 3 phase study looking at treatment experienced individuals showed a modest reduction of virus levels (between .6 and .8 log drop depending on number of baseline mutations). Videx (ddI) will not be recommended for use with Reverset due to elevations of lipase and three cases of pancreatitis using the two therapies in combination. Also, due to drug interactions, Reverset cannot be taken with Epivir or Emtriva. Large Phase III trials will be opening soon.
Tibotec TherapiesTMC-114 is a new protease inhibitor that is showing strong potent antiviral activity in people who are treatment experienced. A 24 week analysis of the drug showed substantial antiviral response and CD4 increases compared to an optimized background regimen. 114 will most likely be the next protease inhibitor approved and will be a welcome new option for people with protease resistant virus. An added benefit of using Fuzeon was also shown in combination with 114, the newly approved Aptivus or Kaletra. (See "New Protease Inhibitor TMC-114" in March/April 2005.)
New non-nucleoside drugs TMC-125 and 278 were also presented in several pharmacokinetic and interaction studies in Rio. Newer oral formulations are being studied as well the effect with food. Larger studies are underway and in planning stages to look at effectiveness. So far these compounds should work against non-nucleoside resistant virus, an important problem with this antiviral class. AIDS activists have lobbied for a first of its kind combination trial with two new investigational agents manufactured by the same company. TMC-114 and 125 will begin enrolling in this fall. The company is also studying a topical microbicide candidate that is very early in development. These agents represent potential hope for treatment and prevention of HIV.
Maturation InhibitorA new drug class that targets a later stage of the HIV lifecycle is slowly gaining attention. In Rio further analysis of the single dose study presented at CROI in Boston showed a long half-life of PA-457 in the bloodstream, and also showed appropriate pharmacokinetic parameters. Watch for a larger Phase II study.
Immune Based Therapy?Human growth hormone got some significant attention in Rio and this time it was not for weight gain. Two separate studies showed increases in thymic mass and total and naive T-cells compared to HAART (highly active antiretroviral therapy) alone or in combination. One study also showed an increase in IL-7, an important immune signaling protein. Study participants received 1.5 mg a day for 48 weeks, or their HAART regimen by itself for 24 weeks, followed by the addition of 3 mg human growth hormone for 24 weeks, taken as once-a-day subcutaneous injections. So far IL-2 is the only immune based therapy that has made it to Phase III studies. Much more work needs to be done to prove human growth hormone will be useful for immune modulation, which could lead to new focus in research.
SummaryThere were several posters and oral presentations of novel classes and mechanisms against HIV that are all in the basic science phase of research. One thing is true -- the field of HIV research for drugs that may be effective for those in need of new options is here, although it may be years before we will see them at the pharmacy.
Reading through conference abstracts on the flight to Brooklyn for the Black Gay Research Summit, I stumble upon an interesting study done in the poverty stricken African nation of Zambia.
Although the details of the study mentioned in the abstract leave a lot to be questioned, many of the statistics in it alarm me. There is one stat in particular that practically jumps right from the page and onto my lap.
It isn't that 73% of the men in the study reported that they believe that anal sex is safer than having vaginal sex with a woman.
Nor is it the fact that more than 40% of the men who reported having sex with other men by choice also said that they only do it for money.
It isn't even that almost 95% of these men do not know that condoms are used in anal sex, either.
As alarming as those statistics may sound, believe it or not, there is something else in this study that is far more frightening. Of all of the men who reported having sex with other men in Zambia, none of them reported having ever been exposed to MSM (men who have sex with men) prevention or advocacy programs. Not one!
In fact, as the author of the study would later reveal, funds that have been allocated for such programs have been redirected towards other projects, such as prevention for female sex workers, because "HIV is not considered to be an exclusively MSM problem in Zambia."
The author also points out that though sex work is illegal in Zambia, as it is in most parts of the United States, there are still many programs that are directed towards female sex workers. And, although many men cross over into the sex work industry as a means for survival in that country, as we see from the 40% in the study who report only having sex with men for money, there are still no efforts being made at outreach for this incredibly high-risk population.
It is not mentioned whether or not any of the men in the study are HIV-positive or if they have ever been tested for HIV. However, it is estimated that more than 16% of the population of Zambia is known to be infected with the virus and, as is the case in the developing countries, heterosexual contact is cited as the most common mode of transmission
As I head to the "Big Apple" to gather with other African American men to discuss the state of the Black gay population in this country, I think about the progress that has been made at acknowledging the prevalence of homosexual behavior among Black men.
I think about how the lingering effects of denying such a truth have ultimately led to some 50% of Black gay men becoming HIV-positive.
The potential for an even greater tragedy awaits the people of Zambia, and many other countries across the globe, if the masses remain in denial about homosexual behavior and ignorant to the factors that put oneself and others at risk for HIV.
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