Treatment Issues, Vol 11, No 2; February 1997
Dave Gilden

The Reservoirs Drain -- Slowly

The most opportune time for antiviral treatment continues to seem to be shortly after transmission occurs (see Treatment Issues article, Europeans Eye New Drug Cocktails; December, 1995, pages 1, 3-4). This is the period when the immune system is relatively intact. At this point, too, the virus tends to be genetically the most homogeneous -- there are few mutations that would allow it to escape either drug therapy or the immune system. Antiviral therapy can work with the immune response to maximum effect during primary infection, with the immune system mopping up any HIV that survives the drugs.

The most publicized trial (thanks to Time magazine) of therapy during acute HIV is taking place at the Aaron Diamond Center in New York City and the University of Geneva in Switzerland. In presentations at the conference Drs. David Ho, Luc Perrin and Marty Markowitz (abstracts S1, 238 and LB8, respectively) reported on the latest observations from this group which now numbers 36 volunteers on AZT/3TC plus either indinavir or ritonavir. All volunteers so far who have been on therapy for more than five months have seen their viral loads go down to undetectable levels (less than 100, or sometimes 25, HIV RNA copies/ml). These virus levels have not as yet rebounded (for as long as 15 months now), with one exception (see below). Anti-HIV immune responses, as measured by antibody and cytotoxic lymphocyte levels also are subsiding by one year, a further indication of HIV's clearance from the body.

A major worry has been the enormous amounts of HIV concentrated in the lymph nodes and other lymphoid tissue. Nearly all of this virus are free virions trapped on the surface of the follicular dendritic cells (FDCs). It is unknown how long the HIV particles remain viable on the FDCs or what is their potential for infecting new cells. There are also many chronically infected cells, which slowly produce new virus over a period of weeks to years, as well as latently infected cells, whose HIV conceivably could activate itself anytime during the cells' lifetimes. The Aaron Diamond Center study is checking gut-associated lymphoid tissue from its acute infection trial participants and finding no sign of active HIV replication there. HIV DNA does persist within some cells, though, and in three of five individuals, HIV virions (or at least, full-length HIV RNA-based gene sets) were detected by PCR. Given the lack of detectable viral replication, Dr. Ho speculated that this HIV was virus trapped on the follicular dendritic cell. No culturable virus was present in any of the specimens.

The extent that potent therapy clears HIV from lymph tissue, including the FDC-associated viral reservoir, was further described in two other major reports at the Conference. One (abstract LB9) examined tonsil biopsies taken from participants in a Dutch study of the AZT/3TC/ritonavir combination. In ten volunteers treated for six months, the HIV population attached to the follicular dendritic cells fell 2,500-fold while the number of HIV-infected cells fell 200-fold. But even at six months, there still was residual HIV on the FDCs (about 1,000 HIV RNA copies/gram) in six of the volunteers; in five, chronically infected cells were still producing small amounts of HIV.

A second study (abstract LB10), which included five people followed for nearly a year in a trial of AZT/3TC/indinavir, had similar results. Detectable HIV remained in the lymph nodes of all five, including the two who had undetectable blood plasma HIV even by the most sensitive PCR assay (detectable limit of 20 copies/ml). The lymph node HIV, whose level correlated with that found in the blood, was able to replicate, but had developed no added drug resistance in the course of therapy. Two other participants who had interrupted treatment for short periods saw the HIV levels in their lymph nodes rebound sharply, with the accompanying appearance of drug-resistant mutant virus.

Ferreting out the Protected Sanctuaries

Aside from holding out in the lymph nodes due to sheer force of numbers, it has been speculated that HIV may be able to seek refuge in areas that drugs cannot penetrate. Among these are the brain and testes. In the Aaron Diamond acute infection study, white blood cells in the semen were negative for HIV activity by one year of treatment. Although latent HIV DNA was still detected in some cells, these HIV gene sets probably are defective and incapable of replicating. Seminal fluid in this study has yet to be analyzed, but in two other investigations (abstracts 202 and 726), free HIV in seminal plasma did indeed decrease dramatically in people put on highly active antiretroviral therapy (HAART).

[A strong word of caution: Measurement of seminal HIV levels is still in its infancy because seminal fluid interferes with the standard PCR test for viral load. A newer technique, known as NASBA ("Nucleic Acid Sequence- Based Amplification") accurately measures free HIV levels in semen, but only down to 1,000 copies/ml. Everyone warns that the infectivity of HIV-positive men on HAART has yet to be determined and that abandonment of safe sex is not justified. The same goes for HIV-positive women even though, according to preliminary results from one study (abstract 727), vaginal and cervical HIV levels may also respond to treatment in parallel with the levels in blood plasma.]

As far as the central nervous system goes, the Aaron Diamond study plans to check HIV cerebral spinal fluid (via lumbar punctures) as a kind of surrogate for the brain, which obviously would be very difficult to extract samples from. While awaiting these results, a study of AZT/3TC versus d4T/3TC has monitored CSF viral load changes (abstract LB7). In this study CSF viral loads went from detectable to undetectable in all 31 participants (initial plasma viral load averaging about 50,000) after 12 weeks of either regimen. In contrast, one poster at the Conference described a case in which a patient taking AZT/3TC/indinavir had an undetectable plasma viral load but a very high level in the CSF (abstract 233).

Duration of Treatment: Years or Decades?

In one report, Katherine Luzuriaga, M.D., of the University of Massachusetts described clearance of HIV in a set of fraternal twin infants who became infected with HIV at birth (abstract 725, which also described four other babies who did not fare as well). Both twins were treated with AZT/ddI/nevirapine, and their plasma viral loads fell to below 20 copies/ml (again, the limit of the ultrasensitive PCR). Unfortunately, one of the twins rebounded at 16 months -- after 11 months of undetectable HIV. He recovered after switching to AZT/ddI/ritonavir, but the question remains, how long must anti-HIV treatment persist before you can feel secure, let alone terminate therapy?

Dr. Ho now estimates that treatment must be continued for at least 2.5 years, with HIV completely suppressed the whole time, before patients and doctors can even think about stopping HIV regimens. (This is the point at which he will ask his trial participants to consider such a move.) His estimate is a prediction based on the decay of HIV levels so far. That decay is a two-phased affair that starts with a rapid drop-off for the first few weeks, apparently due to the rapid death of most HIV-producing cells. Few newly infected cells replace them because the potent drug therapy protects most cells from HIV. The quick dive in HIV is replaced by a gradual tapering off, as the virus trapped on the FDCs, latently infected cells and infected cells chronically producing low amounts of virus gradually peter out as sources of free HIV.

The latest amendments to Dr. Ho's estimate of HIV clearance, scientific as it may seem, is based on a mere eight treatment-naive trial participants receiving AZT/3TC/nelfinavir. Even within these eight there are significant variations, and looking at a larger number of patients might uncover some people whose HIV tapers off at an exceptionally slow rate, adding years to the estimate of how long treatment must last to be sure of eliminating HIV.

But to Keith Henry, M.D., a noted AIDS researcher who directs the AIDS clinic at St. Paul, Minnesota's public hospital, "These results are interesting, but they reflect the conditions in clinical trials, not those of the real world. People have complex treatment histories and don't always take their drugs on schedule. We may have to treat patients for decades, or forever, to keep HIV under control."

Drug Resistance and Outcome

One of the strongest determinants of eventual treatment outcome is drug resistance and its associated HIV mutations, which is influenced by a person's treatment history. (See in particular abstract 584 on the deleterious effect of AZT resistance on outcomes in ACTG trial 175.) The phenomenon of cross-resistance means that the resistance HIV develops to one compound may make it less sensitive to other antiviral compounds, even those it has yet to be exposed to.

One study (abstract 9) looked at the prevalence of drug resistance-conferring mutations in 99 Iowans whose HIV isolates were gathered from 1993 to 1996. Of 32 patients with a history of reverse transcriptase inhibitor therapy, 72% had resistance mutations to a range of nucleoside analogs (particularly AZT) and NNRTIs such as nevirapine. Only five of the 65 individuals without prior treatment had such resistance mutations (four out of five involved AZT resistance). Especially noteworthy was the fact that 26 of the 99 had one or more mutations that are known to facilitate resistance to protease inhibitors even though no one had taken any drug of this class. And of course, therapy, which was carried out without any knowledge of the genetic resistance profile of patients' personal HIV, frequently included drugs that might not work, or at least not work for long, in the individuals taking them.

The Retrovirus Conference had mixed news in regards to which drugs might succeed against HIV that has evolved resistance to particular antiviral agents. Abbott Laboratories is readying for human testing a protease inhibitor that, preliminary tests indicate, suffers comparatively little from cross-resistance with the current inhibitors (see article Protease Inhibitors: Resistance, Resistance, Resistance; page 5). Also, contrary to fears in some quarters, treatment with 3TC and the resulting resistance (generated by a mutation at reverse transcriptase gene 184) does not seem to reduce the activity of ddI or ddC (abstract 588). Conversely, there was a warning that multiple resistance mutations arising from exposure to other protease inhibitors can reduce the power of Agouron Pharmaceuticals' nelfinavir. This new protease inhibitor, now being considered by the FDA for marketing approval, had been touted as immune from such cross-resistance. Similarly, the experimental and very potent nucleoside analog 1592U89 from Glaxo turns out to share resistance mutations with ddI, although the significance of such cross-resistance in humans has yet to be established. High-level resistance to 192U89 has not yet been observed.

Reduction in Hospitalizations, Mortality

Whatever the long-term complexities, the immediate results of the new combination therapies seem good: several reports at the Retrovirus Conference detailed a reduction of hospitalizations or deaths occurring over the past year. For example at New York's St. Vincent's Hospital, which contains the largest AIDS clinic in the city (and whose director, Gabriel Torres, M.D., is Treatment Issues' medical consultant) AIDS hospitalizations are down 10% from a year ago (abstract 264). For New York as a whole, the daily number of deaths per day has fallen by half in the past year, from an average of 20.9 to 10.1 (abstract 376). French doctors also found a sharp decline in AIDS-defining illnesses in four medical centers that rapidly adopted HAART regimens as compared to two medical centers that have prescribed such treatment less frequently. The first four centers were estimated to be saving $650,000 monthly as a result (abstract LB12).

These declines in illness may be related to earlier diagnosis of HIV and better overall medical care for opportunistic infections as well as the introduction of more potent HIV medications. Nonetheless, they are in line with clinical trials that have documented similar OI reductions in people with advanced disease when their current antiviral regimen is strengthened. In particular, the one-year CAESAR trial (abstract 367), which enrolled people with CD4 counts of 250 or less, added 3TC to volunteers' prior treatment (AZT, AZT/ddI or AZT/ddC) and measured a 50% reduction in OIs and death during a year's follow-up. Likewise, a meta-analysis of 22 trials enrolling 13,280 previously treated volunteers (abstract 562) found that mortality rates were halved by therapies that included 3TC or a protease inhibitor, at least for the first year. ddI, ddC or d4T seemed to produce less benefit.

Is the cup half-full or half-empty? It all depends on which side of the 50% line you find yourself. In any case, the cup is leaky. For advanced patients, who are in immediate danger of serious opportunistic infections, long-term disease stability will depend on the immune system's unexplored ability to reconstruct itself once HIV levels are kept down. There were anecdotal reports at the Conference of individual resolution of some conditions after commencing HAART. Among these conditions were chronic cryptosporidiosis, progressive multifocal leukoencephalopathy (PML), Kaposi's sarcoma and wasting syndrome, but these diseases may depend on HIV or HIV-induced inflammation for stimulus.

The reduction in hospitalizations and OIs could well be a temporary blip. At this point the only prudent conclusion one can draw is that therapy against HIV has to continue for years with the present range of drugs. Any therapy you commence may lose effectiveness at some point, even if it appeared highly potent and tolerable, on average, in clinical trials. So if you start on drugs A, B and C, -- you should plan which drugs D, E and F you can switch to -- if at all possible.

Those with long, complex treatment histories may have used up their present options, and those with AIDS do not have the luxury of planning ahead. Both groups already depend on the development of new antiviral (and anti-OI) agents to keep them stable. For some of the major therapy reports at the Retrovirus Conference, see the following pages.

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