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Highlights From the 2001 Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC)

March 2002

The following are highlights from ICAAC held in December in Chicago.

Comparison of Two Once-Daily Regimens

Preliminary results were presented from the FOCUS study, which compares saquinavir (Fortovase) + ritonavir (Norvir) taken once a day to efavirenz (Sustiva), which is also taken once a day. FOCUS enrolled 161 people who received either 1,600 mg of saquinavir + 100 mg of ritonavir or 600 mg of efavirenz. Both groups also received two nucleoside analogue drugs. Volunteers had not previously taken anti-HIV therapies and had an average viral load of about 56,000 copies HIV RNA and CD4+ cell counts averaging 350. After 24 weeks, the results were as follows:

% <400 copies HIV RNA71%84%
% <50 copies HIV RNA 60%81%
SQV = saquinavir
RTV = ritonavir
EFV = efavirenz

More people taking the saquinavir/ritonavir combination discontinued the study because of side effects than those taking efavirenz. The most common side effects included nausea, diarrhea and vomiting. Interestingly, there were no differences in total cholesterol, LDL (bad cholesterol), HDL (good cholesterol) or triglycerides between the two groups.

A previous study compared the two different versions of saquinavir (Invirase and Fortovase) in combination with ritonavir. Volunteers achieved similar drug levels of saquinavir in the blood that resulted in similar anti-HIV responses. However, people on the Invirase combination had fewer side effects. There are now plans to look at the Invirase + ritonavir combination as part of a once-a-day regimen.

Results From the Antiretroviral Pregnancy Registry

An analysis of the Antiretroviral Pregnancy Registry shows that there is no increased risk of birth defects among the children of women taking anti-HIV therapies during pregnancy. This international registry requires healthcare providers to report anti-HIV therapy use during pregnancy. The overall prevalence of birth defects was three per 100 live births, which is similar to the general population. There was also no difference in the risk of birth defects between taking anti-HIV therapies during the first trimester of pregnancy compared to the second or third trimester.

Most doctors encourage women to use caution in taking any therapy during the first trimester of pregnancy, as this is when the risk of side effects and resultant birth defects is of most concern, at least in theory. It is thus encouraging that anti-HIV therapy taken during this important time did not result in an increased risk of birth defects. Even still, there are therapies commonly used in the treatment of HIV disease that should not be used by pregnant women because of serious concerns about birth defects These include, but are not limited to, efavirenz (Sustiva) and all of the azole drugs, such as fluconazole (Diflucan), etc.

Second-Line Therapy With Tipranavir

A small study shows that the new protease inhibitor tipranavir is active as part of a second-line regimen. This study enrolled 63 people, all of whom were experiencing a viral load rebound on their current protease inhibitor-containing regimen. Participants with an average viral load of about 32,000 copies HIV RNA and CD4+ cell counts of about 300 received two different doses of tipranavir and ritonavir (500 mg tipranavir + 100 mg ritonavir or 1,250 mg tipranavir + 100 mg ritonavir, all taken twice a day) or ritonavir + saquinavir (both dosed 400 mg twice a day). In addition, all participants added two new nucleoside analogue drugs (NRTIs). The results after 16 weeks, though not statistically significant, were as follows:

 500 mg TPV1,250 mg TPVSQV/RTV
% <400 copies HIV RNA39% 55% 40%
% <50 copies HIV RNA22% 35% 30%
TPV = tipranavir
SQV = saquinavir
RTV = ritonavir

Somewhat surprisingly, even though people were experiencing a viral load rebound, a large number of people did not have any protease inhibitor-related resistance mutations on entry into this study. This suggests that the reason for drug failure in those cases was probably resistance to the nucleoside analogues being used, not the protease inhibitor. Not surprisingly those with no protease inhibitor-related resistance mutations had better anti-HIV responses.

The higher dose of tipranavir is not going to be pursued in future studies because of excess side effects, including nausea, diarrhea and vomiting. Instead, lower doses of tipranavir (500 mg and 750 mg) will be studied in combination with either 100 mg or 200 mg of ritonavir.

Second-Line Therapy With Atazanavir

Results from a small study shows that the protease inhibitor atazanavir (Zrivada) also has activity when used as part of a second-line regimen. Eighty-five people with an average viral load of about 16,000 copies HIV RNA and CD4+ cell counts of about 300 and who were experiencing a rebound in viral load participated in this study. Almost all had previously taken a protease inhibitor [most were on either nelfinavir (Viracept) or indinavir (Crixivan)]. Volunteers received either two different doses of atazanavir and saquinavir (400 mg atazanavir + 1,200 mg saquinavir or 600 mg atazanavir + 1,200 mg saquinavir all taken once a day) or ritonavir/saquinavir (both dosed 400 mg twice a day). The saquinavir formulation used in this study was Fortovase. Laboratory studies show that there is good synergy when atazanavir is used in combination with saquinavir. The results after 24 weeks were as follows:

 400 mg ATV +
1,200 mg SQV
600 mg ATV +
1,200 mg SQV
% <400 copies HIV RNA53%40%38%
ATV = atazanavir
SQV = saquinavir
RTV = ritonavir

More people had to discontinue taking saquinavir/ritonavir because of side effects. Additionally, people on that regimen had significant increases in triglyceride and cholesterol levels whereas people on either atazanavir doses had either no change or a slight decrease in those laboratory markers.

HIV Drug Resistance in the United States

Blood samples from the HIV Cost and Service Utilization Study (HCSUS) were used to try to estimate the prevalence of HIV drug resistance in the United States. This study collected 1,906 samples of which 36.6% had HIV RNA levels below 500 copies and were assumed not to have any drug resistance. Resistance testing was performed on almost 1,100 blood samples. Seventy-eight percent of these samples were found to contain resistance to at least one drug, with the most common being 3TC (lamivudine, Epivir). This translates to an overall prevalence rate of 50%, when all of the samples are included.

Of the samples that had resistance performed, 70% were resistant to one or more of the nucleoside analogue drugs, 42% to one or more of the protease inhibitors and 31% to one or more of the non-nucleoside drugs. Of greater concern is the finding that 51% of the samples were resistant to drugs in two or more classes of anti-HIV drugs and 14% were resistant to at least one drug in all three classes of anti-HIV drugs. Additionally, 20% of the people who said that they have not previously taken anti-HIV therapies had detectable resistance to at least one drug.

Anti-HIV drug resistance was significantly associated with more advanced disease and the lowest CD4+ cell count but not current CD4+ cell count. Additionally, the prevalence of HIV drug resistance was associated with greater access to healthcare and anti-HIV therapies. (Men were more likely to have HIV drug resistance compared to women; as were gay men compared to other risk groups; and people with private insurance and people with higher educational status OR more formal education compared to people with lower educational status OR less formal education.) This should be expected since to a certain degree, resistance is related to the length of time a person uses therapy. Groups that have been on therapy longer, or who have traditionally had better access to therapy, are also more likely to develop resistance with time.

While this study raises important warnings about the frequency with which resistance is developing, many media reports have exaggerated its findings. Most reports failed to acknowledge that with more than 15 drugs now on the market to fight HIV, it is often possible to find combinations that will work for most patients, despite resistance to some of the drugs. Obviously, the more drugs a person is resistant to, the harder it gets to find a fully active combination. Nonetheless, even combinations that fail to fully suppress HIV have still been shown to produce a clinical benefit. Thus, resistance is a growing concern, but it does not mean people are beyond the reach of treatment.

Additionally, new treatments are now becoming available which seem to work despite resistance to previously used drugs. Drugs that overcome prior resistance at least to some degree include tenofovir (Viread), lopinavir (Kaletra) and other protease inhibitors boosted by ritonavir as well as several drugs likely to be approved in the next 18 months, including T-20, tipranavir and perhaps atazanavir.

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