Suffer the Children
CD4 count and viral load do predict HIV progression in pediatric patients
For a variety of reasons -- including a reluctance on the part of the pharmaceutical industry to enroll younger patients in studies of investigational drugs -- most of the clinical studies conducted in the early years of the AIDS epidemic were open only to adults. As a result, we often had a good idea of how adults would respond to a particular drug or drug combination long before we had any data on how pediatric patients responded to these treatments. During this period those who provided care to infants, toddlers, and preadolescents with HIV disease were often obliged to extrapolate standards of care and parameters of success or failure from data gathered in trials that involved no children.
Fortunately, the F.D.A. now routinely approves the use of new antiretroviral drugs in pediatric patients -- if the pharmacokinetic data are available in children and efficacy has been shown in adults. Furthermore, a new F.D.A. regulation will require that all new drugs be studied simultaneously in adults and children.
For these young patients and their care providers, a report in the January issue of The Pediatric Infectious Disease Journal sheds some much-needed light on the thorny question of how to predict disease progression in children. For two years, a team of researchers from Duke University followed 86 children with HIV. Over the course of the study 22 of these children developed an AIDS-defining illness or died.
The Duke team reports that CD4 cell count and viral load proved to be reliable predictors of disease progression in these pediatric patients. Children who began the study with low CD4 counts and high viral loads were at much greater risk of developing AIDS: 92% of those with CD4 counts below 5% and viral loads above 100,000 developed C.D.C.-defined AIDS or died after an average of 179 days, while only 4% of the children with CD4 counts above 15% and viral loads below 100,000 progressed to AIDS.
What this means for you:
Based on what we now know about disease progression in adults with HIV, the fact that low CD4 counts and high viral loads put pediatric patients at high risk of disease progression comes as no surprise. This study and several others have finally provided us with benchmark CD4 and HIV RNA values to predict disease progression in children. Normal CD4 counts are considerably higher in infants and toddlers than they are in adults, and those normal values change as young children grow up. This means that the guidelines for when to initiate treatment or begin prophylaxis that are based on adult CD4 counts are not applicable to younger patients.
Interpreting viral-load levels in children is even more difficult, chiefly because the values are so high in infants and decline very slowly in the first years of life. After establishing the value of CD4 cell counts and viral-load measurements as surrogate markers of disease progression in children with HIV, my colleagues and I were also able to suggest tentative treatment guidelines for young patients with HIV disease. Our data, which complement those of other investigators, suggest that a viral load above 100,000 in a child with HIV disease mandates a change in therapy.
Go for the Burn
Weight lifting does not increase viral load
Training with weights has often been recommended as a good way for people with HIV to build muscle mass in order to counteract or stave off AIDS-related wasting, which can consume muscle mass. Some have voiced concern, however, that the increase in caloric burn that accompanies intense weight training might lead to an increase in viral load. A report delivered at the Experimental Biology '98 Conference in San Francisco in April suggests that this is not the case. Doctors from Tufts University studied 25 people with HIV who were taking part in weight-training programs. Tests done on these volunteers' blood before and after 15-minute training periods showed that rather than increasing viral load, the training actually caused a slight decrease. Further reports on this subject are expected at this summer's 12th International Conference on AIDS in Geneva, Switzerland. A number of ongoing studies are specifically investigating the effectiveness of strength training as a means of combating wasting syndrome, and we will report those results in the August issue of AIDS Care.
Taking It to Heart
New information on protease inhibitor therapy and unusual fat deposits
In the February issue of AIDS Care we reported that a surprising number of people on combination antiretroviral therapy seemed to be developing large fatty deposits on their belly, buttocks, neck, and face (see "Combination Therapy Can Lead to Unusual Fat Deposits," Vol. 2, No. 1). Dubbed "protease paunch" when it appeared on the lower abdomen and "buffalo hump" when it occurred across the back of the neck, this curious side effect of combination therapy was initially regarded as more unsightly than worrisome. The condition was attributed to unknown metabolic changes; whether it posed significant health problems was unknown.
A French research team subsequently reported a different problem in some of their patients on protease inhibitor therapy -- a loss of fat from places on the body that normally have significant fat pads. Doctors at Hospital La Grave in Toulouse observed 32 people on multidrug therapy that included indinavir (Crixivan®). Over the course of the study, eight of the participants lost fat in one or more of these locations, all sites where body fat usually accumulates: the cheeks, around the cheekbones, the sides of the face near the ears, and on the legs, buttocks, and abdomen. These effects were noted after treatment of variable duration, ranging from two months to two years of therapy, and they resulted in an appearance like that commonly associated with the AIDS wasting syndrome. Here too the likely cause of these physical changes was thought to be a protease-inhibitor-induced alteration in metabolism -- particularly the metabolism of fat.
It now appears that an even more serious fat-related problem may be occurring as a result of protease inhibitor therapy. Doctors at the University of Minnesota have just reported two cases of accelerated coronary artery disease in patients on protease inhibitors. They treated a 26-year-old man and a 37-year-old man, both with low CD4 cell counts and high viral loads despite combination anti-HIV therapy that included a protease inhibitor. Both were admitted to the hospital for chest pains and both, despite their relative youth, were found to have advanced arteriosclerosis.
To test the theory that protease inhibitors might be causing this problem, the Minnesota team evaluated 124 other patients who were receiving protease inhibitors. They found that 33% had elevated lipid (fat) concentrations in their blood. They also noted that 64% of the 116 patients in another study showed metabolic abnormalities after an average of ten months of protease inhibitor therapy. Those abnormalities primarily involved fat metabolism, and they manifested as increases in cholesterol, C-peptide, insulin, and triglyceride levels. Based on these data and their own observations, the Minnesota researchers advise people taking protease inhibitors (and their care providers) to be aware of the possibility that protease-inhibitor-containing antiretroviral therapies may contribute to coronary artery disease.
What this means for you:
While protease inhibitors have proven to be a tremendous benefit for many people with HIV, they are still relatively new drugs and we do not yet know the full range of their side effects -- particularly their long-range side effects. Nevertheless, combination antiretroviral therapy that includes one or more protease inhibitors is currently the best available treatment for HIV disease.
When reports of "protease paunch," "buffalo hump," and other unusual accumulations of body fat first surfaced, the thinking in some quarters was that these fatty deposits were more of a cosmetic problem than a clinical concern. Now that we have preliminary data showing that long-term use of protease inhibitors may be associated with accelerated coronary artery disease in relatively young patients, we must confront the possibility that we are dealing with a more serious underlying disturbance in fat metabolism.
It is abundantly clear that research in this area must be a priority. In the meantime, patients on anti-HIV regimens that contain a protease inhibitor should consult with their care providers about taking steps to delay or treat arteriosclerosis. Patients and providers may reach the joint decision that it would be wise for the patients to make adjustments in their dietary habits and exercise patterns that are similar to those made by people without HIV who are prone to coronary artery disease due to genetic predisposition or other risk factors. Reducing animal fat in the diet, getting regular exercise, and not smoking may all be advisable precautionary measures for such individuals. In situations where life-style changes alone do not bring about reductions in lipid levels, cholesterol-lowering drugs should be considered as a therapeutic option.
A New Treatment for TB
Recently approved drug has a convenient dosing schedule
The first new anti-tuberculosis drug in 25 years has been recommended for approval by a Food and Drug Administration panel, and while this agent has not been specifically recommended for TB patients with HIV, they may want to consider the new drug as a treatment option. Hoechst Marion Roussel's Priftin® is not actually a brand-new drug; rather, it is a long-acting formulation of the standard TB drug rifampin. Currently, rifampin is taken twice a day by people fighting tuberculosis. Priftin needs to be taken only twice a week.
This convenient dosing schedule makes the new formulation especially appealing to people with HIV -- who must already remember to take 20 pills or more a day -- but those taking Priftin will have to be especially vigilant about sticking to the drug's twice-a-week schedule. Because doses are so widely spaced, missing a single dose of the new formulation will be more likely to lead to a relapse -- or even the development of drug-resistant strains of TB.
Not Perfect, But Good Enough
CD4 counts can rise dramatically even when viral loads do not drop to undetectable levels
A decade ago the HIV numbers game was based on CD4 counts: a stable CD4 count was good; a fluctuating CD4 count was worrisome; a falling count was cause for grave concern. Today, people with HIV are once again playing the numbers as if numbers told the whole story -- but this time the game is based on viral-load measurements. An undetectable viral load has become the Holy Grail of HIV treatment, now that we have potent drug combinations to suppress viral replication (and accurate assays to measure viral load).
More people win the viral-load numbers game than win the lottery, but not everyone on combination therapy comes up a winner. Indeed, the goal of maximally suppressive therapy -- a viral load so low that it cannot be detected by the commercial assays now in widespread use -- has proved unattainable, or unsustainable, for many people with HIV.
What does that mean? If you fail to win the grand prize in the new HIV numbers game, does that mean you are failing to derive any benefits from your multidrug regimen? That answer seems to be no; even people who never achieve an undetectable viral load may experience a certain amount of immune reconstitution -- and this immune rebound is reflected in their CD4 counts.
In a recent letter to the editor of The New England Journal of Medicine, a doctor at Boston Medical Center reports on the progress made by two patients who have failed combination therapy -- if failure is measured only in terms of viral load. One patient was diagnosed with AIDS in 1992; at that time his CD4 count was less than 40. In late 1996 this individual began a regimen of nelfinavir (Viracept®), ddI (didanosine, Videx®), 3TC (lamivudine, Epivir®), and d4T (stavudine, Zerit®). The other patient was diagnosed in 1993 with a CD4 count under 30, and he began treatment with ritonavir (Norvir®), saquinavir (Invirase®), ddI, and d4T in early 1997.
Neither of these patients ever achieved an undetectable viral load; in fact, both viral loads remained relatively high. Nevertheless, both individuals have won the old HIV numbers game: their CD4 counts have rebounded (to 526 and 375 cells, respectively) and neither has experienced any opportunistic infections since they began their four-drug regimens.
What this means for you:
The HIV RNA assay is an invaluable clinical tool for all those who treat people with HIV infection. It has enabled us to measure viral activity more directly and more precisely than was once possible -- and this, in turn, has permitted us to individualize therapy to a degree that was heretofore impossible. The downside of all this, if there can be said to be one, is that providers and patients alike have begun to focus on viral load as the definitive gauge of response to therapy. The case studies cited above offer further evidence that viral load is only one way of measuring how well a particular individual is responding to a particular therapy. It remains to be seen if the dramatic increases in CD4 counts seen in these two patients will prove to be durable, but the fact that such significant rebound was seen in the absence of complete viral suppression suggests that it may be possible to effect some degree of immune reconstitution even in patients who do not achieve undetectable viral levels.
Another Benefit of Suppressing Viral Replication
Combination therapy may stave off further bouts of CMV retinitis
People with HIV who have CD4 counts below 100 are at risk of developing cytomegalovirus retinitis, an eye infection that is the leading cause of blindness in individuals with advanced HIV disease. Prophylaxis against CMV should be considered for all people with HIV who test positive for CMV and have CD4 counts below 50. (For a clear, concise assessment of state-of-the-art treatments for this feared OI, see "Better Treatments for CMV Retinitis" in the February 1998 issue of AIDS Care.)
Once a case of CMV retinitis has been treated successfully, it is standard practice for that person to continue to take anti-CMV drugs to prevent further bouts of infection and further damage to the treated individual's retinas. The results from a study recently completed in Spain indicate that this practice may no longer be necessary for certain patients. The Spanish data suggest that people with HIV who have experienced a strongly positive response to maximally suppressive therapy may eventually be able to discontinue so-called secondary prophylaxis against CMV.
In the study, individuals who had overcome an initial bout of CMV retinitis were given three months of highly active antiretroviral therapy in addition to their anti-CMV medication. At the end of that three-month period, those who had CD4 counts over 150, viral loads of less than 200, and negative CMV cultures stopped taking their anti-CMV medication. Nine months later, all seven of the patients who discontinued CMV treatment were still CMV-negative and had CD4 counts higher than 150 and viral loads below 200. These findings confirm those of a team from the University of California at San Diego, which published the first report of discontinuation of therapy in HIV-positive patients with CMV infection.
What this means for you:
CMV retinitis, like disseminated MAC infection, was once regarded as an incurable AIDS-related OI. When an individual developed either of these persistent infections, the best that providers and patients could hope for was long-term suppression of the infection. Eradication of the infection was seldom if ever possible, recurrence was inevitable, and the eventual failure of all known treatments was to be anticipated.
In the February issue of AIDS Care, I reported that my colleagues and I at San Francisco General Hospital have apparently succeeded in eradicating disease in a small group of patients with disseminated MAC (see "HAART Therapy Leads to Resolution of MAC Infection," Vol. 2, No. 1). In this instance, as in the Spanish study cited above, patients were able to discontinue treatment of their AIDS-related OI because they responded so well to highly active antiretroviral therapy, or HAART. In such individuals it is not uncommon to see CD4 counts rebound by 100 cells or more, and the best responders often have their viral loads drop below the level of detection of the commercial assays that are currently in widespread use.
Patients who experience a dramatic rise in CD4 counts and a concomitant drop in viral load on combination antiretroviral therapy clearly achieve some degree of immune reconstitution. We do not yet know how much immune function is regained, but studies like these suggest that even partial restoration of the immune system confers some protection against many AIDS-related OIs.
The Spanish data, like all such reports on the ancillary benefits of highly active antiretroviral therapy, should be interpreted with caution. My colleague Dr. Mark A. Jacobson, the author of "Better Treatments for CMV Retinitis" in the February 1998 issue of AIDS Care, has seen patients who developed recurrent CMV infections after they began highly active therapy -- and after their CD4 counts rose well above what is regarded as the "breakthrough" point for cytomegalovirus infections. However, these patients developed active CMV infection shortly after they began combination therapy, suggesting that they had subclinical CMV disease prior to the initiation of HAART.
The AIDS Clinical Trials Group will soon begin enrolling subjects in a study designed to establish the safety of discontinuing secondary prophylaxis against recurrent CMV infection. Until studies like this one can demonstrate that discontinuing maintenance therapy is both safe and effective, providers should continue to follow the U.S. Public Health Service guidelines for secondary CMV prophylaxis.
Judith A. Aberg, M.D.
San Francisco General Hospital
Diminished libido is a problem for many people with HIV, and erectile dysfunction and impotence are not uncommon in those with advanced disease. HIV-positive men who report reduced sexual drive or impaired sexual function are often helped by testosterone injections -- which have the additional benefit of reversing some of the symptoms of AIDS-related wasting. For these men, Viagra® may prove beneficial. Taken an hour before sex-play is initiated, 50 mg of Viagra helps men with a history of sexual dysfunction to attain and sustain an erection.
The phenomenal number of prescriptions being written for this new drug suggest that it is also being used by men who have normal libidos but who hope to enhance their sexual performance. Men who frequent dance clubs routinely ingest controlled substances of dubious manufacture to alter their mood and amplify their sexual energy. It is reasonable to assume that they will experiment with Viagra in these venues. Indeed, anecdotal reports suggest that this experimentation is already well under way.
What all HIV-positive men who take Viagra need to know is that this drug should not be used concurrently with amyl nitrate and butyl nitrate, more commonly known as "poppers." In clinical settings, these drugs are used to diagnose heart disease. In altered form they are legally sold over-the-counter as solvents -- but they are used almost exclusively to enhance sexual pleasure by stimulating cardiac function.
There are minor chemical differences between pharmaceutical nitrates and over-the-counter nitrites, but both are contraindicated in individuals taking Viagra. In combination the two can lead to a precipitous drop in blood pressure.