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IDSA Conference Briefs (Infectious Disease Society of America)

Paul Volberding, of San Francisco General Hospital, opened the oral presentation on HIV/AIDS on Sunday September 14, 1997.

Hospices in San Francisco have been closing. At SF General Hospital, 8-12 new cases of CMV retinitis per quarter were appearing. This entire year only 4 cases have been presented and all in individuals fresh off the street who had never before had therapy. There have been no new cases of breakthroughs for patients previously treated for CMV retinitis. In some places, some physicians were very cautiously stopping maintenance therapy in patients who have been successfully treated with potent anti-HIV therapy and who continue to respond well to therapy. (Editorial note - I presume that significant increases in CD4 to a certain level would be necessary for a doctor to consider stopping CMV retinitis maintenance therapy.)

From reference to the MACS data compiled by Dr John Mellors and others, he said that "by combining CD4 and viral load we can identify that essentially everyone has a discernible risk of progression...when we look at the IAS and PHS guidelines it is appropriate that only in the most optimal group, those with > 750 CD4 and undetectable viral load, do we see a clear reason not to recommend therapy. In essentially every other case it is thought that therapy should be considered if not necessarily recommended immediately."

Although we intuitively knew this before, the MACS data indicates "the higher one's viral load is, the more rapidly the CD4 count will decline."

Two nucleosides as first line therapy. Volberding went on to comment on the use of a double nucleoside regimen, such as AZT/3TC or d4T/3TC, as a first line therapy, rather than using a potent triple therapy, such as indinavir+2 nucleosides. He referred to the Altis study data reported by Dr Cristine Katlama at the 4th Retrovirus Conference in January 1997. He said, you get a reasonable effect when you use a double nucleoside combination therapy in naive patients, but that effect is weakened severely when patients have been previously treated. More than a 10-fold loss of activity resulted when study participants had prior exposure to nucleoside analogues, usually with AZT/ddI or AZT/ddC. So, the strategy of starting with 2 nucleosides and thinking that later on you could switch to 2 other nucleosides and add a potent protease inhibitor really is, I think, challenged by this data. If you do that, your second line therapy is going to have to work with much less assistance from nucleoside analogues than if you had gone ahead and used potent triple therapy up front."

(Editorial note- In the Altis study, participants received d4T+3TC. Those with no prior nucleoside experience had a reduction in viral load of 1.66 log from baseline to week 24. Those with nucleoside experience had a 0.66 reduction in viral load at week 24. The data from Altis was reviewed in the July issue of our newsletter, NATAP Reports, which is available now on our web site; or, by contacting our office for a hard copy.)

Geno- and pheno-typic testing. Although they are being used more, these tests still have the problem of not very accurately to telling what a patient might be best treated with. If a patient has been heavily treated in the past but not recently, these tests are very good at looking at the dominant virus (most prominent mutations), but not very good at looking at the memory of resistance in a person. Still, drug histories, viral load, and response to therapy are very important in making treatment decisions.

He said viral load should be used as the primary measure for initiating therapy. The goal of therapy should be to lower viral load to undetectable by the most sensitive assay available by using a potent triple therapy regimen.

Finally, he said that HIV is a specialty disease. We need definitions and standards for monitoring treatment by physicians. We should have a training and credentialing process to accomplish this goal.

HIV Detection in Semen 6 Months after the Addition of Indinavir to Combination Therapy (Abstract #16, Ken Mayer, MD, and others)

Dr Mayer said, advanced HIV immunodeficiency has been associated with sexual transmission of HIV. In several studies, HIV has been more readily detected in high concentrations in blood and semen in those with advanced disease, but the issue can be more complex as illustrated by two presentations following this section dealing with nucleoside resistance and transmission from mother to newborn.

In several studies, combination therapy has been associated with decreases in seminal and plasma viral load. But the actual viral load may differ between the blood and semen of the same person. Mixed findings were also observed in the results of this study.

There may be potential for drug resistance virus to be sexually transmitted and that potential is a concern that emerges in this study.

Semen is complex in that it has three compartments. Spermatazoa is suggested not to be a major reservoir for HIV DNA or HIV RNA. Leukocytes, which are primarily CD4s or macrophages or monocytes, may be a significant virus reservoir for HIV DNA provirus or cell associated RNA. The seminal plasma may often contain cell free HIV RNA.

The purpose of the study was to evaluate the change in HIV load in blood and semen for 22 HIV-infected protease inhibitor-naive men. Blood and semen HIV load were assessed before and after the participants changed their therapy from a double nucleoside regimen to a protease inhibitor regimen. Participants changed at least one nucleoside, some changed two nucleosides, and added indinavir. Investigators wanted to see if seminal HIV after more potent therapy would most likely be detected as cell associated proviral DNA, intracellular RNA or cell free RNA in seminal plasma.

22 asymptomatic men were enrolled between April and August 1996. 2 had KS, 1 had oral hairy leukoplakia, 1 had thrush, and 1 had recurrent HSV. They had been stable on a double nucleoside regimen for at least 6 months. Their median baseline CD4 was 255 (range 81-632); at the time of the study, the 1st generation bDNA viral load was the only one available, and had a lower limit of detection of 10,000 copies/ml; 64% of the participants had viral load < 10,000 copies/ml.

At baseline, 60% (13/22) participants had HIV detected in semen by 1 of the 3 tests used; that is, a large portion of the men had HIV in semen detected by 1 of the three tests, but not by all 3 of the tests. 14 participants had plasma viral load < 10,000 copies/ml. Although it wasn't statistically significant, HIV was more often detected in semen in men with plasma viral load > 10,000 copies/ml (7/8), then those with plasma viral load < 10,000 copies/ml (6/14).

Summary of results. For several men, HIV load decreases paralleled a decline in viral load plasma; but, in some cases that did not occur, as the plasma viral load decline was not parallel with a change in semen HIV load. After 6 months on study treatment, HIV DNA was found in 4/20 individuals, and it was statistically significant; but only one person had detectable RNA. This person also had detectable DNA. It's important to remember that just because RNA was not detected that does not mean RNA wasn't present; it may have been detected by a subsequent test. In addition, the presence of DNA has the potential for causing transmission of virus, more so particularly if therapy fails and viral load rebounds. Safer sex is still required.

The maximum cell free seminal RNA was 400,000 copies/ml before the treatment change and 10,000 copies/ml at 6 months; maximum cell associated semen, RNA was 70,000 copies/ml before therapy change and 27,000 at 6 months; and, the maximum seminal proviral DNA was 80,000 at baseline and 3,000 after 6 months. This is the maximum level detected for any one person at the time points at which levels were checked.

For 75% of the men, the plasma viral load was undetectable, < 500 copies/ml (bDNA, 2nd generation test), after 6 months 2 of these men with undetectable plasma viral load had provirus DNA detected in semen. This brings up the concern about transmission of resistant virus.

3/8 men with plasma viral load > 10,000 copies/ml at baseline had seminal HIV DNA at 6 months compared to 1/14 with plasma viral load < 10,000 copies/ml at baseline.

After 1 month there were decreases in the number of individuals who had HIV detected in semen. One person consistently over the 6 month period had HIV detected in all 3 compartments. Several individuals were undetectable at 1 month but detectable again at 6 months.

Four individuals had detectable provirus DNA at 6 months. One individual had less than a 1 log reduction in plasma viral load at 1 month, had no detectable proviral DNA, but was detectable at 6 months. A second individual had his plasma viral load decrease by > 1 log at 6 months

Two other individuals had undetectable plasma viral load (< 500 copies/ml) at 6 months but detectable proviral DNA at 6 months. The HIV DNA in semen for these two is being examined for resistance mutations.

One patient at baseline had a CD4 of 144 and a viral load below 10,000. He started therapy with AZT/3TC/indinavir and switched to d4T/3TC/saquinavir due to intolerance and non-compliance. At 6 months, his CD4 was 122, and plasma viral load had dropped from 40,000 to 900 copies/ml; but, semen cell free RNA was 10,000 copies/ml and cell associated HIV RNA was 27,000 copies/ml.

The Effect of AZT Resistance and Viral Load on The Risk of Vertical Transmission

Briefly, it was reported that an AZT resistance mutation can increase the risk of transmission. The risk of having a mutation increases with having a lower CD4 count, and/or higher viral load.

Dr Bob Coombs presented data (abstract #17) from a study of pregnant women enrolled in the 076 study. In 076 pregnant women were randomized to receive a specially designed protocol of AZT therapy or AZT placebo. It was found that the 076 AZT protocol regimen significantly reduced the rate of transmission of HIV from mother to newborn compared to those pregnant women who did not receive AZT.

The aim of Coombs' study was to see if AZT resistance at the time of delivery increased the risk of transmission to the newborn. He found little evidence that there was an association between AZT resistance at delivery and the risk of transmission, but there was little evidence of the development of AZT resistance at the time if delivery.

However, the conclusions he can draw from the data are limited, because the group of women he studied were mostly AZT-naive, had high CD4 counts (550 CD4) and low viral load (19,000 copies/ml for women who transmitted HIV in the study, 6,000 copies/ml for women who did not transmit) and received a limited duration of AZT treatment in the 076 study. (Editorial note- Since their was a low risk of developing resistance by delivery it would be unlikely to find an association between resistance and transmission.)

However, he found that low level or high level AZT resistance could develop although there was a low percentage for that occurring. He found viral load at delivery was a significant predictor of transmission. There was a 4-fold increased risk of transmission for every 5-fold difference in viral load.

By contrast, Dr Seth Welles presented data (abstract #18) from a study of women who received AZT for their own personal treatment. Additionally, they had more advanced HIV (at a moderate stage of disease progression) than those women studied in the Coombs study. Their median baseline CD4 count was 315, and viral load was about 25,000 copies/ml. He reported AZT resistance did cause an increased risk of HIV transmission from a pregnant mother to her newborn, in the group he studied.

Welles reported he found that-

ACTG 333

This was one of the first trials to look at the complex issues related to sequential use of protease inhibitors and cross-resistance. The goal of the study was to observe the change in plasma viral load upon replacement of saquinavir hard-capsule (HGC) with either saquinavir soft-gel capsule (SGC) or indinavir. Dr Michael Para reported the preliminary findings (abstract #21).

The baseline median viral load was 14,462 copies/ml. 25% had viral load below 2,500 copies/ml and 25% had > 48,000 copies/ml.

This was an open-label protocol. Participants had a median of 105 weeks prior saquinavir experience. They were on stable anti-HIV therapy for at least 2 months and were randomized to receive indinavir, saquinavir SGC, or to continue the saquinavir hard-capsule, and were requested not to change their nucleosides during the first 8 weeks of the study. After 8 weeks participants were permitted to change nucleosides.

After 8 weeks, individuals receiving saquinavir HGC were switched to indinavir. At week 8, subjects randomized to saquinavir SGC or indinavir were evaluated for their HIV RNA response. The primary objective of the interim analysis was to examine the 8 week changes in viral load to ensure they were large enough for the study to continue. The guidelines developed by the study team suggested that if either arm did not show a reduction in viral load of at least 0.7 log compared to the saquinavir HGC, the arm would be considered for termination.

Median baseline viral load and CD4 (just prior to change in protease inhibitor) was 4.3 log (about 20,000 copies/ml) and 222 cells, respectively. 6% had a viral load < 200 copies/ml at baseline.

Results. The data is based on 72 study participants. After 8 weeks of treatment the changes in viral load and CD4 from baseline were-

Protease Inhibitor Viral Load CD4 Count
Saquinavir HGC no change no change
Saquinavir SGC -0.27 log +37 cells
Indinavir -0.56 log +22 cells

In the indinavir arm, 25% had > 1 log reduction in viral load; and, 25% had no reduction. In subjects with detectable viral load (> 200 copies/ml) at baseline, 2/24 (8% ) in the SQV HGC arm, 4/22 (18% ) in the SQV SGC arm, 9/21 (43% ) in the indinavir arm had undetectable HIV (< 200 copies/ml). At week 8, 2/22 (8% ) in the SQV HGC arm, 2/20 (20% ) in the SQV SGC arm, and 7/19 (37% ) in the indinavir arm had HIV below detection (200 copies/ml).

Weeks 8-24. After the 8 weeks on SQV SGC, the subjects who had no viral response were switched to indinavir and over the next 4 months there was no clear trend. The other subjects who had a fall in viral load or a response at week 8 were continued on the SGC and you see a slow rise in viral load. 4 subjects who had no viral load response to indinavir were switched to SGC and showed a small response at best. Para reported that there was a subset of indinavir recipients who had a sustained reduction in viral load through week 24. Para said, definitive conclusions about changes in viral load over weeks 8-24 could not yet be reached. But, clearly viral load responses were disappointing. Viral genotyping and drug susceptibility testing are ongoing and are expected to be reported.

The investigators proposed several potential reasons for responses that were less than seen in other trials of a protease inhibitor plus 2 nucleosides: (1) the subject's extensive protease inhibitor experience (105 weeks prior saquinavir experience) may have altered HIV's drug susceptibility (cross-resistance), (2) a single antiretroviral agent, the protease inhibitor, was switched, (3) the subjects were receiving SQV HGC and stable nucleoside therapy at entry when they made the protease inhibitor switch so that the change in viral load is incremental to the suppression from the SQV containing regimen.

At the International Workshop on HIV Drug Resistance, Treatment Strategies and Eradication conference in St. Petersburg, Florida this past July there was much discussion about protease inhibitor cross-resistance. Agouron again showed their data which suggests that pretreatment with nelfinavir will not cause cross-resistance, but there is a difference of opinions about this issue among researchers. Some researchers at St. Petersburg reserved judgment about whether or not first line treatment with nelfinavir would cause cross-resistance to other protease inhibitors if nelfinavir resistance emerges. Some believe that all protease inhibitors will have some degree of cross-resistance while others are uncertain. At the ICAAC meeting in Toronto on September 26, 1997, Dr Keith Henry will report preliminary data for individuals who failed nelfinavir therapy in Agouron's study #511 and were switched to a ritonavir/saquinavir double protease therapy. NATAP will report ICAAC highlights on our web site.

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