PI Perspective #19

September 1996     View PDF

Update on Antivirals

Results from studies of antiretrovirals presented at the XIth International Conference on AIDS in Vancouver were uniformly encouraging. Studies using 3-drug combinations were a major focus of the conference and the quality of the new results were so good as to be unimaginable even a year ago. These studies show that people using the drugs consistently and as prescribed had the longest benefits. People who were less consistent and careful developed resistance to the drugs more rapidly resulting in a loss of benefit from therapy. Most of these studies looked at people who had not taken antiretroviral therapies. People who have been on long-term prior antiretroviral therapy are unlikely to receive the same kind of response unless they are able to start multiple new therapies simultaneously.

Indinavir (Crixivan)
Follow-up results from a study of 97 people with CD4+ cell counts from 50 to 400, who had been on AZT for at least 6 months prior to the study were encouraging. People received either AZT + 3TC, indinavir alone or AZT + 3TC + indinavir. Early results from this study were reported in PI Perspective #18. The activity of the 3-drug combination has been sustained for a year with over 80% of people below the level of detection by PCR (HIV RNA below 500). See Table 1.

Table 1: Indinavir triple combination
Study Group	# below detection @ week		Median VL drop (logs) @ week		Med CD4+ increase @ week
	24	48	24	48	24	48
IDV	11/27 (41%)	5/9 (56%)	-0.8	-1.6	106	158
AZT + 3TC	0/27 (0%)	0/8 (0%)	-0.6	-0.4	14	14
AZT + 3TC + IDV	27/30 (90%)	6/7	-2.2 (86%)	-2.3	127	218
VL=viral load;      IDV=indinavir

Due to antiviral and CD4+ responses seen to the 3-drug combination, all participants were offered the 3-drug regimen after 24 weeks. The results in table 1 include only people who stayed on their originally assigned regimens and do not include people who switched to the 3-drug regimen.

The lasting antiviral effect from the 3-drug regimen is very encouraging considering that people entering this study had been on AZT for two and a half years on average and had developed AZT resistance. However, everyone began 3TC for the first time during the study and there is no evidence that anyone on the 3-drug combination developed 3TC resistance. The effect may be due to indinavir and 3TC, as 3TC is unable to “rejuvenate” AZT until the virus develops 3TC resistance.

Another indinavir study compared different doses of the drug when used alone. Surprisingly, the viral load of about half the people on the study have remained below the level of detection (for this study, it was defined as HIV RNA below 200). Seventy people received 800mg three times a day (2.4g), 1,000mg three times a day (3.0g) or 800mg four times a day (3.2g) of indinavir.

These results, shown in Table 2, were unexpected because in previous studies of lower dose indinavir monotherapy, resistance developed rapidly resulting in a loss of antiviral activity. The antiviral response is the most dramatic and sustained yet seen with any drug used alone. The data suggest that it may sometimes be possible to maintain effective therapy and long-term control of resistance without using a triple combination. The results from 3-drug combinations, however, are more consistent and monotherapy runs a greater risk of causing resistance. It may someday be possible to predict who can benefit from monotherapy and who will need multi-drug combinations.

Table 2: Indinavir monotherapy
Study Group	# below detection @ week		Median VL drop (logs) @ week		Median CD4+ increase @ week
	24	48	24	48	24	48
2.4g	6/14 (43%)	7/13 (54%)	-2.3	-2.6	80	85
3.0g	8/18 (44%)	5/14 (36%)*	-2.6	-1.2	105	135*
3.2g	7/16 (44%)	2/8 (25%)*	-2.5	-1.5*	145	190^
VL=viral load;      *week 44;      ^week 40

Ritonavir (Norvir)
Preliminary results of a study combining ritonavir with saquinavir show that this may be a good combination for people who have failed or are intolerant to the nucleoside analogues. People with 100 to 500 CD4+ cells received 400mg ritonavir and 400mg saquinavir twice daily, 600mg ritonavir and 400mg saquinavir twice daily, 400mg ritonavir and 400mg saquinavir three times daily or 600mg ritonavir and 600mg saquinavir twice daily. The six week data for the first two groups are shown in Table 3.

Table 3: Ritonavir / Saquinavir combination
Arm 400mg SQV	VL drop (in logs) @ week		% with <200 RNA @ week		% <200 RNA or >2 log VL @ week		CD4+ rise @ week
	2	6	2	6	2	6	6
400 RTV +	2.0	2.5	25	40	30	70>	90
600 RTV +	2.0	2.7	20	60	25	90	110
VL=viral load;      SQV=saquinavir;       RTV=ritonavir

Side effects were similar between both groups, most commonly mild tingling around the mouth (80%), diarrhea (69%), fatigue (43%), nausea (37%) and flushing (37%). Most of the side effects were reported as mild, but many people believe the seriousness of ritonavir side effects have been consistently understated. Two people had to discontinue therapy due to side effects.

It is still too early to know how long the antiviral response will last or if there will be side effects which may be caused by the accumulation of one or both drugs in cells or tissue. Also, the optimal doses for this combination remains to be determined.

Two other studies looked at the effectiveness of AZT + 3TC + ritonavir for people in early disease who had not previously used antiviral therapy. The first study assigned one group to start AZT + 3TC + ritonavir while the other group first began on ritonavir alone then added AZT + 3TC after 22 days. The goal was to determine if there are fewer side effects or differences in antiviral response when AZT and 3TC are initiated later compared to when all three drugs are started at once. Thirty-three people with CD4+ counts above 500 participated in this study. There were similar viral load and CD4+ cell responses in both groups. After 8 weeks there was an average 3 log (1000 fold) decrease in viral load in both groups. Those receiving immediate 3-drug therapy had a 130 CD4+ cell rise after 8 weeks while the group receiving deferred AZT + 3TC had a 175 CD4+ cell increase. Because of the small numbers and short time period, it is impossible to say if these are significant differences. It is also too early to tell if the delayed addition of AZT + 3TC reduces the risk of side effects.

The other study examined AZT + 3TC + ritonavir for “primary infection” (the first 90–120 days of HIV-infection) to determine if early, aggressive antiretroviral therapy can change the course of HIV disease. Of the 12 people participating, three withdrew because of drug side effects or inability to comply with taking the three drugs. One person could not tolerate ritonavir and was given indinavir instead. Preliminary results show that all 9 people remaining in the study have viral loads below the limit of detection after 5 months of therapy. Also, they have had an average rise of 200 CD4+ and 100 CD8+ cells. Those who have fewer than 900 copies of HIV RNA for 9 continuous months will be asked to undergo lymph node biopsies to determine if there is virus in the lymph nodes. Based on the outcome, some may go off therapy to see what happens. Read more about the theory behind this study in the HIV Eradication article.

On Using Ritonavir …
Ritonavir use has been associated with many side effects, especially during the first month of use. Abbott Labs, the manufacturer, reports that the high rate of initial side effects may be caused by excessive levels of ritonavir accumulating in the bloodstream in the first few weeks of use. This effect corrects itself in subsequent weeks and this sometimes (but not always) alleviates the side effects. Abbott Labs suggests that the following recommendations may reduce the most common side effects associated with initial use of the drug:

• To more easily adjust to the new medication, start on 300mg twice a day for 2 days, then increase the dose to 400mg twice a day for 2 more days, 500mg twice a day for 2 days and finally up to the recommended dose of 600mg twice a day.
• Preliminary data suggest that the step up from 500mg to 600mg is the most difficult, with many people reporting they are unable to tolerate the highest dose. When this is the case, the 500mg twice a day dose should be used. THIS SHOULD BE THE LOWEST DOSE USED since a lower dose may lead to more rapid development of resistance.

It is not clear whether dosing should be adjusted according to weight, although women and men with lower body weight report unusually difficult times with the drug. For now, no information is available to make such adjustments, though it stands to reason that 200 lb man and a 120 lb woman taking the same dose would result in substantially different levels of the drug in each person.

Some physicians prescribe ritonavir at 400mg 3 times a day and report that this schedule appears well tolerated. Taking ritonavir with a fatty meal may help reduce side effects associated with taste and gastrointestinal distress.

Saquinavir (Invirase)
A recent study comparing saquinavir + ddC to ddC alone or saquinavir alone showed that people on the combination were less likely to progress to disease or die compared to those receiving either drug alone. It enrolled 978 people with CD4+ cell counts between 50 and 300, who had taken AZT previously. Preliminary results from this study are shown in Table 4.

These results are difficult to interpret. Previous studies have shown that ddC or saquinavir alone have so little activity as to be almost placebos. Thus, this study only shows that saquinavir + ddC is better than placebo. The study tells us nothing about how this combination compares to other common 2-drug regimens such as AZT + 3TC, nor can one compare it to the other protease inhibitors. Perhaps the most important message from the study is that even modest decreases in viral load delay disease progression and death.

Preliminary results from a study of 33 previously untreated people with CD4+ counts of 150 to 500, shows potent short-term antiviral activity for AZT + 3TC + saquinavir. After 4 weeks, there was an average 2 log (100 fold) drop in viral load and a 100 CD4+ cell rise. The combination was well tolerated, but two people developed severe nausea. The short-term data are encouraging but the length of the response is unknown. Such small, uncontrolled studies are difficult to compare to other studies.

Nelfinavir (Viracept)
Preliminary results of a study of AZT + 3TC + nelfinavir are promising. Twelve people beginning therapy for the first time participated. One withdrew because of side effects. After 16 weeks of therapy, the remaining 11 had viral loads below detection. They had an average viral load drop of almost 4 logs (10,000 fold) and a 100 CD4+ cell rise. Also, they had complete resolution or marked improvements in ‘soft’ symptoms of HIV disease, such as oral candidiasis and hairy leukoplakia. Common side effects from this combination included mild to moderate diarrhea, nausea and fatigue. The small numbers and the uncontrolled nature of the study, make it difficult to say how this compares to other therapy options.

Table 4: Saquinavir / ddC
Study Group	Median VL drop (logs) @ week 16	Median VL drop (logs) @ week 24	Mean CD4+ rise @ week 16	# deaths	# deaths and/or progression
SQV	0.1	0.1	5	34	77
ddC	0.35	0.3	15	28	85
ddC + SQV	0.6	0.5	38	9	46
VL=viral load;      SQV=saquinavir

3TC (Lamivudine, Epivir)
A 3TC study was stopped early because those receiving the drug showed survival benefits and reduction in disease progression. Almost 1900 people with CD4+ counts from 25 to 250 participated. They could be on AZT, AZT + ddI or AZT + ddC on entering the study. They received either a placebo, 3TC or 3TC + loviride (a non-nucleoside reverse transcriptase inhibitor) in addition to their other therapy. The 3TC alone arm included twice as many people as either of the other two arms. See Table 5.

Table 5: 3TC / Loviride
Study Group	Mean VL drop (in logs) @ week 4	Mean VL drop (in logs) @ week 24	Mean CD4+ increase @ week 4	Mean CD4+ increase @ week 24	# deaths and/or progression
placebo	0	0	0	-20	81 (17%)
3TC	1	0.6	40	10	80 (9%)
3TC + loviride	1.2	0.8	40	10	38 (8%)
VL=viral load

Increases in viral load seen at week 24 suggest the onset of drug resistance. Still, people receiving 3TC saw a 54% lower risk of progression or death compared to those on placebo. The addition of loviride to 3TC did not result in any benefit, probably because resistance occurred very quickly. People receiving 3TC had better viral load and CD4+ cell responses than people receiving placebo. About 5% of people on placebo, 3% of people on 3TC + loviride and 2% of people on 3TC had to leave the study because of side effects.

These results further support the predictive value of viral load and CD4+ cell increases seen in the four 3TC studies used for accelerated approval of this drug. Additionally, an analysis of those studies combined showed a reduced risk of disease progression for people receiving 3TC.

1592U89
Preliminary results from a study of 1592U89, a new nucleoside analogue, shows very potent activity. Eighty people were given 200mg or 400mg of 1592U89 3 times a day for 4 weeks, followed by 8 more weeks of 1592U89 alone or with AZT. After 4 weeks of 1592U89 alone, people had a 1.5 to 2.2 log drop in viral load and a 79 to 127 CD4+ cell rise, which were sustained through the end of the study. The most common side effects were nausea, weakness, headache and rash. The drug may be more potent than many 2-drug nucleoside combinations, and will be studied with other drugs. Glaxo-Wellcome is unlikely to present the drug for FDA approval until late 1997.

Commentary
The goal of antiretroviral therapy is shifting toward driving viral load levels below detection by the new tests. This does not mean that HIV has been completely eradicated. These studies suggest that the most likely way to achieve this is to use 3-drug therapy (preferably of drugs that have not been used previously), although a 2-drug combination or even a single drug may be potent enough to achieve this level of viral suppression. Triple-drug combinations are probably required to knock down viral load to undetectable levels if viral loads are very high (100,000 or higher). Getting viral load down to such low levels may be a difficult task, but once there, drug resistance may be greatly delayed.

IAS Guidelines for Viral Load Testing

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