The origin of HIV was probably the most publicized report from the conference. At the Keynote Lecture Sunday evening, Dr. Beatrice Hahn, of the University of Alabama at Birmingham, told attendees that the source of HIV-1 is a particular species of chimpanzees native to west central Africa. Though researchers have theorized that primates might be the origin for HIV-1 for quite some time, Dr. Hahn provided evidence of the actual species of chimpanzees, known as Pan troglodytes troglodytes. This subspecies is confined to the same region of West Africa where the oldest cases of HIV-1 have been found. Humans in Africa have hunted chimpanzees for food for a long time and could have easily acquired the virus through contamination with chimpanzees blood. The most important piece of knowledge gathered from this discovery is that the chimps are asymptomatic. Hopefully, if researchers can learn why these chimpanzees do not develop disease, we might be able to use this information to develop a vaccine, or at least more effective treatments. However, there are some serious potential obstacles in studying these chimps. The animals are in danger of extinction due to the growing trade and killing of "bush meat" in West Africa. Not only could this result in the loss of the best study subject we've found; but it also indicates a continuing, and growing, threat for additional exposures to infectious chimpanzee blood to West Africa's people.
The importance of adherence to antiretroviral regimens was the subject of numerous presentations. One, which was especially noteworthy, came from Dr. Susan Swindells of the University of Nebraska in Omaha. A study of 84 patients on PI therapy showed that strict adherence to the regimen was vital for successful treatment. After three months of therapy, 81% of the patients maintained over 95% adherence to their regimen. This group of individuals had complete viral suppression (an undetectable viral load). Of the patients with a 90% to 95% adherence rate, 64% had viral suppression. Of the patients with an 80% to 90% adherence rate, only approximately 50% achieved viral suppression. When adherence rates dropped to 70% to 80%, viral suppression dropped to 25%. And finally, in those patients who adhered to their regimen less that 70% of the time, viral suppression dropped to only 6%. Clearly this study shows the need for increased efforts to help patients adhere to their chosen regimens.
Transmission of drug-resistant virus is becoming more and more prevalent as shown by three different studies. Last summer at the 12th World AIDS Conference in Geneva, a study was presented showing the first documented case of drug resistant virus being transmitted through male-to-male sex. At the conference in Chicago was presented the first documented case of heterosexual transmission of a drug-resistant strain of HIV. In this case, a strain of HIV that was resistant to two non-nucleoside reverse transcriptase inhibitors (NNRTIs) was transmitted to a female patient through unprotected heterosexual intercourse. Dr. Judith Feinberg, of the University of Cincinnati in Ohio, described the case of a 19-year-old woman who was infected by her partner with his strain of HIV that was resistant to both delavirdine and nevirapine. The resistance was verified by both genotypic and phenotypic tests. It was found that her partner had been poorly compliant with his therapy, which included delavirdine.
Dr. Scott Wegner of the US Military HIV Research Program in Rockville, Maryland measured the frequency of drug resistance in 114 drug-naïve subjects who were known to have been infected with HIV in the preceding three years. Again, by genotypic and phenotypic testing, 21% of those patients showed resistance to either reverse transcriptase inhibitors or PIs, even though they had never taken antiretrovirals.
In another study of 69 recently diagnosed patients who were given both genotypic and phenotypic resistance tests before receiving any antiretroviral therapy, Dr. Susan Little of UC San Diego determined drug resistance in 28% of that population.
These studies show the increasing spread of drug-resistant virus. This trend will only get worse as more people go on combination therapy, develop resistance either from non-adherence or other means, and then transmit the virus to others. Safer sex, and safer using, guidelines may be more important than ever as this virus continues to spread.
Crixivan in triple therapy kept HIV undetectable in most patients at three years! One arm of Merck's 035 study has been following a small group of patients on a three-drug regimen of Crixivan, AZT and 3TC for over three years, and has found approximately 63% of these patients to still be undetectable (less than 50 copies/mL). Although this is a small study with only 22 patients still remaining (originally 33), it has been going on for over three years and has been subject to a lot of scrutiny. It does seem to give some optimism that it is possible to find an effective regimen that will sustain its effectiveness for at least three years.
The Atlantic Study is the first trial to directly compare the safety, activity and durability of the three different available classes of AIDS drugs within combination regimens. There are three different arms to this study: d4T/ddI/3TC (all nucleosides), d4T/ddI/nevirapine (two nucleosides and one NNRTI), and d4T/ddI/indinavir (two nucleosides and one protease inhibitor (PI). While only preliminary data is available at 24 weeks (main analysis will be performed at 48 weeks, then follow-up to 144 weeks), the results so far are fairly compelling. At 24 weeks, the arm containing the PI is doing just slightly better than the arm containing the NNRTI, which in turn is doing a little better than the all nucleoside arm. With possible side effects of PIs beginning to show up in many patients, it's encouraging to see fairly similar potent antiviral activity among all three combinations, including the two protease-sparing arms. However, this is very preliminary data, and long term effects are still yet to be determined.
Efavirenz vs. indinavir: a protease sparing regimen? DuPont has more data on study #006, which is comparing the use of efavirenz/AZT/3TC vs. efavirenz/indinavir vs. indinavir/AZT/3TC. This study had gotten a lot of attention when presented last summer in Geneva. It was the first study to show an NNRTI-containing regimen actually achieving as good as, if not better than, reductions in viral load than a PI regimen. With new data now presented at 48 weeks into the study, the results are still looking good. The efavirenz-containing arm had consistently better results in lowering viral load than the other arms. It should be noted that all patients in this study were both PI and NNRTI naïve.
Some of the major concerns regarding efavirenz (other than price) are nervous system disorders. In DuPont study #655, nervous system symptoms and/or rash were experienced by 54% of those patients in the arm receiving efavirenz (600 mg. q.d.) versus only 27% in the control arm. It seems that most of those who did experience nervous system side effects did so in the first two days, and generally those adverse events were resolved within two to three weeks. There was also a high incidence of rash among the efavirenz arm, 28% vs. 18% in the control arm. Most rashes were mild to medium and generally resolved within a few weeks. Side effects were greatly minimized if drug was taken at bedtime.
Hypertriglyceridemia (High Triglycerides, HT) is being seen in many patients taking antiretroviral therapy. The AIDS Research Consortium of Atlanta (ARCA) presented a descriptive study on 745 patients from the Center for Disease Control's Adult and Adolescent Spectrum of HIV Disease project (ASD). All 745 patients had triglyceride data available since January 1996. In patients grouped by their antiretroviral drug experience, the prevalence of HT was significantly greater in patients taking PIs plus nucleosides (15.1%), than either those taking NNRTIs plus nucleosides (6.1%) or nucleosides alone (6.5%).
Substituting an NNRTI for a PI was the subject of numerous studies, due to the rising incidence in side effects from PIs and the complexities of their dosing and scheduling. Most of these trials switched patients from a PI containing regimen to one containing a NNRTI instead. Most of these studies used nevirapine as the NNRTI. Although these studies are very short at only an average length of 12 weeks, all seem to show improvements in metabolic abnormalities, including lipodystrophy. In addition most patients making this switch were able to maintain viral suppression and previous CD4 counts. As encouraging as these results may be, it needs to be remembered that these studies are new and very short, and patients should probably wait to see more long-term data before making any changes to their antiretrovirals.
The reduction of transmission of HIV from mother to child with just one week of AZT and 3TC therapy was one of the most important study results presented at this conference, at least according to this author. The United Nations AIDS Perinatal Transmission (PETRA) Trial is the largest clinical trial ever to examine mother-to-child transmission of HIV. The researchers showed data on 1,357 pregnant women in South Africa, Uganda and Tanzania who either received AZT and 3TC beginning in the 36th week of pregnancy and continued through the postpartum period, received the drugs only at the beginning of labor and continued for one week, or were given them only during labor and delivery. Transmission rates to the newborns were not reduced at all in those women receiving treatment only during labor and delivery. Transmission rates were reduced by 50% for the patients who began treatment at 36 weeks, and were reduced by 37% in those receiving treatment beginning at labor and following for one week. In both arms continuing treatment after delivery, the babies were also treated for the same time period as the mothers. Although the arm representing one week of treatment was not quite as effective as the arm using longer treatment, with the difficulty (or impossibility) of getting these drugs to the people in the developing countries, these results show that we can achieve benefit from a much lower amount of drugs than we thought. Glaxo Wellcome, who manufactures both drugs used in this trial announced that it would lower the price of both AZT and 3TC for developing countries.