More evidence that genes confer protection against AIDS progression
A newly discovered allele, SDF-1, offers twice the protection of other gene variants...
We previously reported that individuals who have inherited a particular genetic mutation, CCR5-Delta32, from both parents seem to remain immune to HIV infection, even after repeated exposures (see "Genetic mutation appears to confer immunity to HIV," Vol. 2, No. 5). Those who inherit the gene from only one parent do develop HIV disease, but in these individuals progression from asymptomatic disease to frank AIDS takes three or four years longer than it does in people who lack the CCR5-Delta32 mutation.
Subsequent research identified variants of two additional cell-surface co-receptors, CCR2 and CXCR4, that appear to play roles in retarding the progression to AIDS. Now the team of investigators at the National Cancer Institute that discovered CCR5 has found another gene variant -- this one named SDF-1, for stromal-derived factor -- that also retards the rate at which HIV infection progresses to AIDS. SDF-1, which is also called pre-B cell growth-stimulating factor, is a powerful chemoattractant. It is the natural ligand for CXCR4, which is one of the surface co-receptors that virulent, late-stage HIV uses to enter cells. When SDF-1 is present, it down-regulates CXCR4 in cells, thereby preventing HIV from entering target cells.
The demonstration that SDF-1 effectively inhibits HIV replication prompted a search for SDF-1 structural gene variants that might influence the transmission or pathogenesis of HIV. In a subgroup of 2,854 patients enrolled in five large national HIV cohorts, Winkler et al. screened 1,354 of the base pairs represented in human SDF-1 transcripts with a series of polymerase-chain-reaction primers and other assays. What they found is that a common mutational variant of SDF-1, SDF-1-3'A -- which occurs in roughly one- third of Caucasians -- affords approximately twice the protection of CCR5 or CCR2 against disease progression and death in HIV-infected patients when it is present in two doses, one from each parent. They also discovered that the protection provided by the two CCR alleles and SDF-1 is additive: patients with both of these protective genotypes avoid AIDS and death longer than those with only one.
Winkler C, Modi W, Smith MW, Nelson GW, Wu X, Carrington M, Dean M, Honjo T, Tashiro K, Yabe D, Buchbinder S, Vittinghoff E, Goedert JJ, et al. Genetic restriction of AIDS pathogenesis by an SDF-1 chemokine gene variant. Science 1998; in press.
Dr. Stephen J. O'Brien, author of "A New Approach to Therapy," the editorial that appears in this issue, and an author of the paper cited above, comments:
Although the frequency of SDF-1 homozygous protected individuals is low -- less than 5% in the five large HIV cohorts that we studied -- the effect of this genetic variant, when it is inherited from both parents, is quite strong. The protective effect of SDF-1 is more apparent during the later stages of HIV infection, when rapidly reproducing, extremely virulent, T-cell-tropic forms of HIV develop, but the principal effect of SDF-1 may actually involve strong protection against rapid disease progression during the early stages of infection. We know, for example, that approximately half of those with HIV who do not carry the double allele for SDF-1 succumb to AIDS within 10 years of infection. By contrast, less than 5% of those with the SDF-1 homozygote genotype develop AIDS in the same period.
The real significance of this discovery is not that certain fortunate individuals, thanks to their genetic endowment, do not develop HIV even if they are repeatedly exposed to the virus, but that we can now add yet another gene variant to the growing list of chemokines that confer protection against HIV infection or retard its progress to full-blown AIDS. The discovery of these genetic variations opens a promising new avenue of research -- into therapies that prevent infection, or dramatically slow the progress of HIV disease, by mimicking the antiretroviral action of these variants.
In the October 1996 issue of HIV Newsline we reported that a team of researchers in the Laboratory of Genomic Diversity at the National Cancer Institute had discovered a gene that appeared to confer protection against HIV infection in persons homozygous for the variant allele and that slowed disease progression in persons heterozygous for the allele.
The N.C.I. team -- which was headed by Dr. Stephen J. O'Brien, author of the editorial in this issue -- announced that this mutant gene, CCR5-Delta32, seemed to provide complete immunity against HIV infection to the one individual in 100 who has inherited the mutation from both parents; for the one individual in every five who has inherited the mutant gene from one parent, it confers resistance to disease progression. The surprisingly high incidence of partial resistance could explain why some individuals survive for many years with active infection.
A team of researchers from the French Pediatric HIV Infection Study Group recently reported the first data on the effects of CCR5-Delta32 on vertical transmission and disease progression in children. Misrahi et al. followed 512 children born to seropositive mothers. Of the 512 children, 276 proved to be infected with the virus. All were tested for the CCR5 mutation. The one infant who had inherited the mutant allele from both parents was persistently HIV-negative. Of the 49 infants who had inherited CCR5-Delta32 from only one parent, half eventually tested seropositive -- evidence that heterozygosity for the gene does not prevent vertical transmission.
However, heterozygosity for CCR5-Delta32 did appear to slow the progression of HIV disease. At 36 months, 28% of the children with a pair of normal CCR5 genes showed stage C symptoms of disease, while only 9% of the children with one mutant gene had progressed that far. By age eight, only 11% of the children with normal genes had not yet developed stage B or C symptoms of HIV disease, whereas fully 49% of the children with one mutant CCR5 gene had no evidence of disease progression. The French team's findings mirror results seen in studies of adults.
Highlights of the 5th Conference on Retroviruses and Opportunistic Infections: A special three-part report to readers of HIV Newsline
The 5th Conference on Retroviruses and Opportunistic Infections, which convened in Chicago in the first week of February, offered clinicians new insights and information on the technology used to detect replicating HIV and to measure the immune response to infection. For example, the team of investigators who evaluated the two-drug combination of DMP-266 (efavirenz, Sustiva®) and indinavir were able to demonstrate the potency of this NNRTI-protease inhibitor combination, but more to the point they showed that the study participants who failed this treatment were those who failed to achieve the lowest level of replicating virus.
This finding suggests that "below the limits of detection" is, in fact, a moving target: what was once regarded as an acceptably low level of HIV RNA may not be low enough, given that viral load, even at fairly low levels, seems to correlate with response to therapy. It may be necessary to lower the present limits of detection of most commercial assays. If the level and durability of viral suppression is indeed predictive of a durable virologic response -- and is predictive even at levels that currently fall "below the limits of detection" of these assays -- then we will need a new and considerably more sensitive generation of assays to guide us in managing our patients on suppressive therapy.
Several presentations made at the conference demonstrated that dried-blood-spot specimens can be used to detect HIV RNA and HIV DNA in a large population. This technique is wonderfully stable, and these quantitation methods may be very useful in developing countries, where standard viral-load measurements are impractical. In addition, these methods may prove useful in detecting HIV in very small samples of blood and plasma (such as the stored specimens from neonate heel-sticks), and in detecting the presence of HIV infection among groups in diverse geographic locations.
A study with significant public-health implications demonstrated the utility of the dual-EIA antibody test. This system takes advantage of the time-sensitive development of HIV-specific antibodies. Newly infected individuals who are past the stage of symptomatic acute infection -- or who never manifest symptoms of acute infection -- can be identified as recently infected (that is, infected within the past 180 days) if their serum reacts to standard third-generation antibody tests but does not react to the detuned EIA.
This system of dual testing can be implemented in a variety of clinical settings to identify those with recently acquired infection. Such individuals tend to have high levels of circulating virus, and this makes them highly contagious. Identifying these highly efficient transmitters of HIV, and treating their primary infection in an aggressive manner, may help us to reduce "community viral burden" and thus limit the spread of infection. In addition, this system may be an excellent way to trace people who have been put at risk of HIV through contact with a recently infected individual, since most people are likely to remember their most recent sexual liaisons. These people can then be contacted and encouraged to submit to testing to determine if they have recently been exposed to HIV.
Another important presentation at the conference dealt with rapid HIV testing. There is considerable interest in providing HIV antibody results to clients while they are in the clinic, rather than at a follow-up visit. Providing results to clients immediately, instead of after a one- or two-week delay, may lead to reduced rates of new infections, since the window between testing and notification can be a window of opportunity for transmission.
The additional advantage of rapid HIV testing is that it permits the rapid initiation of maximally suppressive therapy, which reduces viral burden and, with it, the enhanced risk of transmission that occurs during periods of high viremia.
James O. Kahn, M.D.
Associate Director, AIDS Program
San Francisco General Hospital
A key theme of the 5th Conference on Retroviruses and Opportunistic Infections was the potential for reconstitution of the immune system after it has been damaged by HIV. One of the highlights of the meeting was a state-of-the-art lecture on this topic delivered by Dr. Bruce D. Walker of Massachusetts General Hospital. In "The Body Fights Back" Dr. Walker presented detailed information on the immunologic responses of so-called long-term non-progressors, people who have maintained low viral loads and high CD4 counts despite up to 20 years of documented infection.
Dr. Walker's data suggest that these fortunate individuals mount vigorous and sustained HIV-1-specific T-helper cell responses to HIV infection. These T-helper cell responses promote and sustain cytotoxic T-lymphocyte reactions, which rapidly clear HIV-infected cells from circulation -- thus controlling viremia even in the absence of antiretroviral therapy. This critical T-helper cell response to HIV infection has been shown to be less emphatic -- or even absent -- in individuals with rapidly progressive disease. In addition, this response has been found to correlate inversely with viral load in all patients studied.
In light of these discoveries, Dr. Walker and his colleagues sought to mimic this vigorous T-helper cell response by using potent antiretroviral therapy to suppress viremia during acute HIV infection. Their intent was to limit virus-mediated destruction of HIV-specific T-helper cell responses. The group was able to demonstrate, in 11 of 11 individuals treated during the acute stage of infection, HIV-specific T-helper cell responses and robust cytotoxic T-lymphocyte responses, both of which were absent prior to therapy.
Within three to seven months of the initiation of therapy, all 11 subjects were found to have strong T-cell and CTL responses, with corresponding reductions in viral load. It remains to be seen if these individuals have in fact developed the ability to control viremia without antiretroviral therapy in the period since these important immune responses were fostered.
As Dr. Walker emphasized, there appears to be a relatively narrow window of opportunity following HIV infection for interventions designed to bolster immune function. Individuals with chronic infection and progressive disease often fail to mount T-cell and CTL responses, even with aggressive antiretroviral therapy and even when viral loads fall to undetectable levels.
Chronic HIV infection is associated with progressive loss of immune system components and immune function, as demonstrated by loss of CD4 cells, particularly those expressing the naïve phenotype. In addition, chronic infection leads to an increased CD8/CD4 ratio, to perturbation of the T-cell receptor repertoire, and to loss of delayed-type hypersensitivity lymphocyte proliferation responses to new and recall antigens.
The potential for reversal of this immune destruction and dysfunction was addressed by a number of participants in this meeting. At last year's conference Dr. Michael Lederman presented preliminary data from ACTG 315 which suggested that patients with advanced disease (CD4 counts less than 300 cell/mm3) experienced partial immune reconstitution after 12 weeks of potent antiretroviral therapy with zidovudine, lamivudine, and ritonavir, as evidenced by increases in absolute CD4 counts, increases in naïve CD4 and CD8 lymphocytes, and improved responses to functional assays such as the delayed-type hypersensitivity skin-test.
These initial findings were confirmed by the 48-week data from ACTG 315, which were presented by Dr. Elizabeth Connick in early February in Chicago. These data demonstrate a two-phase CD4 lymphocyte response to combination therapy. The first phase consists of rapid increases in both naïve and memory CD4 cells and in naïve CD8 cells -- presumably as a result of the redistribution of cells from lymphoid tissues. The second phase consists of more gradual but persistent increases in naïve CD4 cells combined with decreases in memory CD4 cells and naïve CD8 cells.
The data from ACTG 315 also show that 48 weeks of therapy with this particular three-drug combination produces decreases in markers of cellular activation and decreased apoptosis in tonsillar tissues. These findings were buttressed by Jaramillo et al., who presented data demonstrating a trend toward normalization of the CD4 repertoire following combination therapy lasting more than 15 months. Improvements in immune function were also reported by Markert et al., who found improved lymphocyte proliferative responses to recall antigens and neo-antigens in treated patients.
Despite these significant advances in our understanding of immune reconstitution following maximally suppressive antiretroviral therapy, many questions remain. What role does the thymus play in immune reconstitution? What are the immunologic consequences of viral rebound? Can HIV-specific T-helper cell responses be stimulated in chronically infected individuals? What degree of immune reconstitution will allow for the safe discontinuation of chronic suppressive therapy and primary prophylaxis against such common OIs as MAC, CMV, and PCP? (For a partial answer to this question, see "HAART therapy leads to resolution of MAC infection" in this Newsline section.) It is evident that these questions will shape our research agenda for some time to come.
Kimberly Y. Smith, M.D., M.P.H.
Rush Medical College
The mood at the 5th Conference on Retroviruses and Opportunistic Infections was one of enthusiasm -- and relief -- as presentation after presentation reaffirmed the widespread belief that HAART had drastically reduced the incidence of OIs in patients with advanced HIV disease. These findings accelerate a trend that began before the advent of HAART, presumably due to a combination of earlier intervention, more effective prophylaxis, combination nucleoside therapy, and improved clinical recognition and care.
Michaels, Clark, and Kissinger from New Orleans conducted a retrospective study of a cohort of patients with CD4 counts below 200 cells/mm3. They compared the rates of OIs 18 months before and 18 months after the availability of protease inhibitors. The most striking declines were seen in the incidence of PCP, which fell from 18% to 11.7%, and in the incidence of wasting, which dropped from 9.5% to 4.8%. The investigators did not comment on the role that prophylaxis may have played in effecting this trend.
Dr. Robert Murphy presented an analysis of OI risk based on antiretroviral regimens in 1,057 patients enrolled in the CPCRA 034/ACTG 277 trial, a PCP prophylaxis study. The median CD4 count was 60 cells/mm3 in this cohort, and 49% had a prior AIDS-defining illness. None of the patients were on a protease inhibitor at baseline, but protease inhibitor use increased dramatically during the study: to 9% at 12 months and 72% at 24 months. The clinical event rate declined from 64 per 100 person-years during the first year of the study to 34 during the second year. The most significant declines in relative risk were seen in PCP and in mortality.
Moore and colleagues at Johns Hopkins assessed the incidence rates of OIs and the use of combination antiretroviral therapy in 1,500 patients, and here again the data showed a significant decline in infections. The greatest reduction occurred with CMV, followed by reductions in cryptosporidiosis, toxoplasmosis, MAC, PCP, AIDS dementia, and bacterial pneumonia. Of note, none of the patients with a CD4 count greater than 200 cells/mm3 developed an opportunistic infection.
Dr. Judith Currier presented a very thorough overview of the decreasing incidence of OIs. As she indicated, study after study supports the contention that maximally suppressive antiretroviral therapy has dramatically reduced the number of OIs seen in patients with advanced HIV disease -- but these infections do continue to occur. As my colleague Dr. Steven Deeks noted, a significant number of patients experience "virologic failure" -- rebound of viral load after suppression with HAART -- yet these patients still have stable CD4 counts and have not progressed clinically.
So, what is really going on in these patients? Does HAART really confer protection against OIs? Has immune reconstitution really occurred? This was easily the most controversial -- and most exciting -- topic addressed at the conference. There was compelling evidence presented that the initial increase in CD4 count that is seen with HAART results from peripheral expansion of pre-existing lymphocytes. This rapid expansion is followed, after a year or more of HAART, by a gradual, selective rise in naïve T-cells. What we don't know is how much of the previous memory repertoire is regained after HAART.
What are the clinical implications of this new information? Can we really stop prophylaxis and/or maintenance therapy for OIs in patients who respond well to HAART? Freeman and colleagues presented follow-up data on eight patients with CMV retinitis who discontinued maintenance therapy after their CD4 counts rebounded on combination antiretroviral therapy. These patients still have no evidence of recurrent disease an average of 300 days after the cessation of treatment of their retinitis. In addition, my colleagues and I at San Francisco General Hospital reported on four patients who discontinued MAC therapy after receiving 12 months of macrolide-based antimycobacterial therapy and HAART (see "HAART therapy leads to resolution of MAC infection" in this Newsline section).
We are still faced with many unanswered questions regarding immune reconstitution. OIs still exist. They may be diminished in number and severity, but significant morbidity and mortality does occur. Several clinical trials, ongoing or in development, will address the issue of discontinuing prophylaxis for MAC and PCP and of discontinuing therapy for CMV and MAC. Until they provide us with a better picture of what is happening in these patients, I recommend that clinicians follow the guidelines issued by the Infectious Disease Society of America and continue prophylaxis and maintenance therapy regardless of how high a patient's CD4 count rises.
HAART therapy leads to resolution of MAC infection
Another apparent benefit of maximally suppressive antiretroviral regimens
Prior to the introduction of highly-active antiretroviral therapy, disseminated MAC infection was one of the most common life-threatening opportunistic infections seen in patients with advanced HIV infection. DMAC occurred almost exclusively in patients with CD4 counts below 50 cells/mm3. Prognosis was poor: even with optimal antimycobacterial treatment, median survival was only eight to nine months from the time of diagnosis. Despite the widespread use of a multidrug macrolide-based regimen, relapses were common. There were no reports of microbiologic cure of MAC on this regimen, so the standard of care was to continue treatment for the rest of the patient's life.
The advent of HAART has changed this picture, as it has changed so much about the treatment of HIV infection and its sequelae. A group at San Francisco General Hospital reports that four of their patients who developed disseminated infection when their CD4 counts fell below 50 cells/mm3 have apparently been cured by a combination of HAART plus antimycobacterial therapy for DMAC. After more than a year of antimicrobial therapy and HAART all four were asymptomatic and medically stable. Antimicrobial therapy was withdrawn after both peripheral blood cultures and bone marrow cultures were sterile for MAC. All subsequent cultures on all four patients have been negative (range: 5-10 months), and all four of these patients remain clinically asymptomatic.
Aberg JA, Yajko DM, Jacobson MA. Eradication of disseminated Mycobacterium avium complex (DMAC) in four patients after twelve months anti-mycobacterial therapy and response to highly active antiretroviral therapy (HAART). 5th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, January 31 to February 5, 1998. Abstract 729.
Dr. Judith A. Aberg, an author of this report and a member of the editorial advisory board of HIV Newsline, comments:
To our knowledge this is the first report of the successful discontinuation of antimycobacterial therapy for DMAC in patients with AIDS after presumed immune reconstitution following HAART. There were no reports of microbiologic cure in the pre-HAART era. Although median survival with optimal antimycobacterial therapy in the pre-HAART era was less than one year, our four patients were asymptomatic after one year of combined antimycobacterial therapy and potent antiretroviral therapy, had sterile blood and bone marrow cultures, and had no clinical or microbiologic evidence of MAC relapse up to ten months after discontinuing antimycobacterial therapy. These observations suggest that AIDS-related DMAC can be cured in patients who demonstrate immunologic improvement with HAART. ACTG 393, now in development, will further elucidate which patients can safely discontinue MAC maintenance therapy.
Evidence continues to accumulate that HAART has a significant impact on AIDS-related morbidity. There have been multiple anecdotal reports that HAART has a positive therapeutic effect on such previously untreatable OIs as progressive multifocal leukoencephalopathy, cryptosporidiosis, and microsporidiosis. Torriani et al. have reported that eight of their patients were able to discontinue CMV maintenance therapy on HAART. These patients had a median CD4 count of 39 cells/mm3 at the time their CMV retinitis was diagnosed; at the time their CMV maintenance therapy was discontinued, the median CD4 count was 172 cells/mm3 (range: 63-404).
None of these individuals experienced progression of CMV disease after a mean follow-up of 146 days (range: 72-205). CD4 counts remained elevated (mean: 198 cells/mm3) even though six out of the eight patients had detectable viral load (mean: 40,000; range: 409-423,000). These findings suggest that HAART may restore CMV-specific immunity even in patients who do not achieve complete suppression of plasma viremia.
Studies are needed to further characterize the immunopathogenesis of DMAC, so that those patients at highest risk for disseminated infection can be identified. It would then be possible to target prophylaxis or pre-emptive therapy for that population -- and then discontinue that treatment if HAART restores the immune responses associated with MAC protection. A better understanding of these immune mechanisms would help clinicians predict which patients with DMAC can be expected to be cured of their infection after a course of antimycobacterial treatment, and it would also provide data for the development of immune-based therapies.
Adefovir: The first nucleotide analog
A novel antiretroviral agent shows early promise
The first member of what might be considered a fourth class of anti-HIV agents is now in Phase III clinical trials. Adefovir dipivoxil is a decoy for reverse transcriptase, which mistakenly adds the tri-phosphorylated form of the drug to a DNA chain, thus terminating it. Nucleotides consist of a nitrogen-containing base, a five-carbon sugar moiety, and a phosphate group. Earlier drugs, like ZDV, ddI, and ddC, are analogs of nucleosides, which are the same as nucleotides but without a phosphate group.
Three phosphates are eventually needed to provide the energy to keep the DNA chain growing. The enzyme that adds the first phosphate group is only expressed in certain cells at certain times, a fact that limits the antiretroviral activity of nucleoside analogs. Nucleotides are one step ahead of the game, with the first phosphate already in place. A separate enzyme, one found in a wider variety of cells for longer periods of time, adds the other two phosphate groups.
Since adefovir requires only the more broadly available enzyme, it should be a more versatile drug than the venerable nucleoside analogs. Adefovir was recently assessed in a small, randomized, placebo-controlled trial over a period of 16 weeks. Treatment was for 12 weeks, and patients were re-evaluated four weeks after cessation of any antiretroviral therapy. The 72 patients recruited for this study had a median baseline CD4 count of 339 cells/mm3 and RNA level of 4.9 logs. During the first six weeks of the trial, two-thirds of the participants received drug, of which half took 125 mg once daily and the other half took 250 mg once daily. The remaining patients were randomized to placebo.
After six weeks, everyone was given open-label drug. As a group, the patients had significant prior antiretroviral exposure, with median duration ranging from 2.3 years in the low-dose arm to 3.5 years in the original placebo group. This difference between drug and placebo recipients was statistically significant.
Changes in CD4 counts were not particularly impressive, but after six weeks of therapy there was a small, significant rise in CD4 counts among patients assigned to the 125-mg dose. The authors were puzzled that this benefit was not seen in patients on the higher dose. HIV RNA responses were more consistent.
A statistically significant decline in HIV RNA levels was noted in drug recipients at both dose levels after six weeks. RNA rebounded close to baseline during the four weeks off treatment. Placebo recipients had no change in HIV RNA from baseline to six weeks, but they did exhibit a decline in viral levels after being switched to drug.
Adefovir also has in vitro activity against CMV and other viruses. The authors conducted a subset analysis of 18 patients who had positive CMV titers in semen samples. Of the 13 evaluable patients, all drug recipients (n=10) showed a decrease in semen CMV halfway through the trial. By contrast, the three placebo recipients in this cohort had increases in semen CMV.
The drug appeared to be well tolerated. Nausea was the most frequent adverse effect, and it seemed to be dose-dependent. Four patients in the higher-dose arm left the trial due to drug toxicity; two had nausea and vomiting, one developed dysuria and a genital ulcer, and the fourth patient had fever and chills. No patients in the lower-dose arm discontinued the drug because of adverse effects.
In summary, this agent shows promise against HIV, with possible anti-CMV activity as well. Early results indicate that adefovir is well tolerated, and resistance does not seem to develop rapidly or consistently. It will be interesting to see how well this agent performs in combination with the many other drugs now in clinical use.
Deeks SG, Collier A, Lalezari J, Pavia A, Rodriguez R, Drew WL, et al. The safety and efficacy of adefovir dipivoxil, a novel anti-human immunodeficiency virus (HIV) therapy, in HIV infected adults: a randomized double-blind, placebo-controlled trial. J Infect Dis 1997:176:1517-1523.
Combination d4T and 3TC in patients with prior exposure
A therapeutic option in some patients who have developed resistance to ZDV
Stavudine (d4T) and lamivudine (3TC) are commonly used together because they are known to be synergistic and because they have non-overlapping toxicity profiles. The rationale for their concomitant use is supported by studies that show them to be safe and efficacious in patients with limited prior antiretroviral therapy.
Rouleau and colleagues, working at the University of British Columbia, gave this combination of nucleoside analogs to a group of HIV-infected patients who were failing, or intolerant of, combination regimens that contained ZDV. More than half of the participants had previous experience with one or both of the study medications -- meaning that the study reflects what is commonly seen in the real world of clinical practice.
Of 58 patients recruited for this open-label study, 48 patients were evaluated; 10 others did not complete the trial for various reasons. Two dropped out when they developed rash that may have been associated with a study medication. Mean CD4 at baseline was 135 cells/mm3 and mean viral load was 4.7 logs. One-third of these patients had experienced an AIDS-defining event. ZDV had been taken for a median of 12 months by trial participants, and 30 of the participants also had prior exposure to d4T or 3TC.
During the eight-week trial, subjects received 150 mg of 3TC twice daily and 20-40 mg of d4T twice daily. Neutropenia, associated with 3TC therapy, developed or worsened in 11 patients, but only one needed to discontinue the drug as a result. Twelve patients showed increased liver enzymes, an adverse reaction sometimes seen when patients take d4T, and four of these reactions were indeed considered to be therapy-related. None of the 12 left the trial or suffered adverse consequences. Grade 1 peripheral neuropathy, possibly related to d4T administration, was seen in nine patients. One additional patient developed a Grade 3 neuropathy, prompting discontinuation of study medications.
After two weeks of therapy, HIV RNA levels reached their nadir, with a median decrease of 0.86 log. Over the next six weeks the median RNA level climbed steadily, but it remained well below baseline at eight weeks. By the end of the trial, 16% of patients had undetectable viral load by the Amplicor assay. The median CD4 change was an increase of 30 cells/mm3 above baseline at eight weeks.
The patients who benefited the most from the two-nucleoside combination of 3TC and d4T, as reflected in viral load and CD4 measurements, were those who began the trial with higher CD4 counts, no prior exposure to the study medications, and no AIDS-defining event. However, even those patients with lower CD4 counts, prior exposure to d4T or 3TC, and an AIDS diagnosis showed some response to the d4T-3TC combination, suggesting that it overcomes some degree of therapy-induced resistance. The authors conclude that prior d4T and/or 3TC therapy does not preclude the ability to achieve a response to these two drugs in combination.
Rouleau D, Conway B, Raboud J, Rae S, Fransen S, Shillington A, et al. Stavudine plus lamivudine in advanced human immunodeficiency virus disease: a short-term pilot study. J Infect Dis 1997; 176: 1156-1160.
Dr. Paul A. Volberding, the editor-in-chief of HIV Newsline, comments:
Although the current standard of care for people with HIV is therapy with a combination of at least three antiretroviral agents -- usually two nucleoside analogs plus a protease inhibitor, less often two nucleoside analogs plus an NNRTI -- a significant number of patients are still being treated with a combination of two nucleosides, and a distressing number remain on monotherapy.
Dual-nucleoside regimens are not the most potent or the most appealing of current therapeutic options, but for some patients they may be the best practical choice, especially for patients who cannot obtain or tolerate more powerful antiretroviral drugs. Certainly they are indicated for those who cannot comply with complicated multidrug regimens. For patients who have not begun triple-drug therapy, d4T plus 3TC is a safe and moderately effective therapeutic combination. It will not consistently suppress viral load to undetectable levels, but it does leave patients the option of switching to more potent combinations at a later date. An attractive feature of combining 3TC and d4T is that both drugs are given twice a day and there are no dietary restrictions.
Inadequate diet is a factor in disease progression in IVDUs
Women are at particular risk for OIs and other complications
Poor nutritional status has been associated with decreased survival, increased disease progression, and more frequent development of opportunistic infections in patients with AIDS. Intravenous drug users are at particularly high risk for inadequate nutrition, and this risk factor represents a special challenge for healthcare professionals who treat IVDUs with HIV infection. A new study suggests that female IVDUs with advanced immune suppression secondary to HIV infection are disproportionately in need of interventions aimed at improving their nutritional status.
Baum et al. recruited 82 men and 43 women from a cohort of drug-using HIV-infected individuals followed for the previous nine years. The group was overwhelmingly African-American (88%), with a sampling of Hispanic (8%) and white participants (4%). The mean baseline CD4 value was 407 cells/mm3 for men and 470 cells/mm3 for women, a difference that was not statistically significant. Men and women in the study had comparable dietary intake. However, there were significant differences in the nutritional status of men and women, reflected in different concentrations of micronutrients and proteins in blood samples.
These differences were noted only in patients with CD4 counts below 200 cells/mm3, a relatively small segment of the cohort (28 men and 11 women). Nevertheless, the numbers proved to be of statistical significance. Women with low CD4 counts had lower levels of selenium and of vitamins A and E. Furthermore, sensitive surrogate markers of overall nutrition were diminished in this group of female IVDUs. The average levels of prealbumin in men with CD4 counts below 200 cells/mm3 were 20.8 mg/dl, and the average retinol-binding protein levels were 4.6 mg/dl in this group. The comparable figures among women with CD4 counts below 200 cells/mm3 were 11.3 mg/dl and 2.2 mg/dl, respectively. The reason for these differences remains obscure to the authors, who postulate that it is probably multifactorial. They call for further study to determine the etiology of the differences they noted.
Some studies have shown differences in disease progression and survival between men and women, with the latter group generally having a less favorable course. Other studies contradict this observation. The findings of Baum et al., in this select group of patients with HIV infection, merit follow-up. If they are corroborated, it will be important to assess the reasons for the marked nutritional deficiencies seen in female IVDUs with low CD4 counts, so that specific interventions can be developed.
Tracking HIV in the central nervous system
CSF RNA levels appear to correlate with AIDS dementia
The pathophysiology of HIV in the central nervous system has been difficult to characterize. It is well known that the CNS is a viral reservoir, and because most antiretroviral agents have poor CNS penetration this reservoir represents a major therapeutic challenge in the quest to eradicate HIV infection. A more immediate goal is to understand the relationship, if any, between viral levels in the CNS and the neurological sequelae of HIV infection. Using state-of-the-art viral quantitative techniques, McArthur and colleagues have generated data that move us closer to understanding how HIV affects the tissue of the CNS.
Specifically, this group, which represents a collaboration between researchers at Johns Hopkins, Glaxo Wellcome, and Organon Teknika Corporation, examined the relationship between HIV RNA load and neurologic status in 207 HIV-infected patients. The subjects were recruited from the Multicenter AIDS Cohort Study (MACS) and the neurology clinic at Johns Hopkins in Baltimore. They were divided by clinical neurologic status: 37 patients had a diagnosis of HIV dementia (HIV-D) at baseline, 77 had HIV-associated minor cognitive/motor disorder (HIV-MCMD), and the remaining 93 were without neurological symptoms (HIV-NML). Patients with opportunistic infections of the CNS or cytomegalovirus infections were excluded. When available, frozen, viable CSF samples were used; otherwise participants underwent lumbar puncture. The samples were collected before HAART became the standard of care for patients with HIV infection.
This was the first study to use the nucleic acid sequence-based amplification assay (NASBA) to examine the relationship between neurologic disease and viral load. In this cohort, plasma HIV RNA was isolated with equivalent frequency across the whole clinical spectrum of participants. However, there was a significantly higher percentage of RNA isolated from CSF samples of patients with dementia (81%) versus patients with HIV-MCMD (38%) or those without neurological symptoms (33%).
Viral load in CSF was also significantly higher in the patients with dementia compared to the other two groups, a correlation not observed with plasma RNA measurements. Furthermore, the authors found a correspondence between plasma RNA and CSF RNA levels in patients with CD4 counts below 200 cells/mm3. Plasma RNA levels were not independently associated with neurological symptoms, however.
For the group with CD4 counts below 200 cells/mm3, an association was also found between CSF RNA levels and CSF-ß2 microglobulin levels. This last finding is considered by the investigators to reflect a parallel increase between viral load in the CSF and activation of an immune response. Twenty-two post-mortem brain samples were available for study; only six were from demented patients. The authors found no correlation between HIV RNA levels in the tissue and clinical neurological status.
There is some question as to whether HIV in the CNS is mostly a result of local replication or of trafficking through the blood-brain barrier via white blood cells. The authors assert that the number of white blood cells they observed was insufficient to explain the levels of viral load they measured in CSF with the NASBA assay. They suggest that brain tissue is a significant source of HIV in this compartment.
These findings strengthen the case for CSF HIV RNA as a surrogate marker for HIV dementia and suggest a relationship between plasma RNA and CSF RNA levels in patients with low CD4 counts. In addition, they provide insight concerning the pathogenesis of HIV infection in the CNS.
McArthur JC, McClernon DR, Cronin MF, Nance-Sproson TE, Saah AJ, St. Clair M, and Lanier ER. Relationship between human immunodeficiency virus-associated dementia and viral load in cerebrospinal fluid and brain. Ann Neurol 1997; 42: 689-98.