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August 1998

  1. Protease inhibitors and reconstitution of the immune system
  2. Withdrawing secondary CMV prophylaxis
  3. Two promising new treatments for anal warts
  4. Human papilloma virus and anal cancer
  5. Dramatic decreases in HIV prevalence among Thai military conscripts
  6. Something More You Need to Know About Viagra
  7. Better Treatment for CMV Retinitis: An Update

Protease inhibitors and reconstitution of the immune system

More on the indirect benefits of therapy

Antiretroviral regimens that contain at least one protease inhibitor are remarkably effective at suppressing HIV replication. If that were the end of the story, these drugs would be of limited value to AIDS patients with profoundly compromised immune systems. However, clinical studies and clinical experience tell us that patients with advanced disease derive more benefit from protease inhibitors than would be explained by anti-HIV activity alone. A recently published Canadian study sheds light on the indirect effects of protease inhibitor treatment on cell-mediated immune functions.

Angel et al. recruited 42 patients with CD4 counts ranging from 100 to 500 cells/mm3 and no prior use of protease inhibitors. The median viral load in this cohort was 4.74 logs. Patients were randomized to receive one of four regimens containing ritonavir plus saquinavir. One patient dropped out during the first week of the study, so only the remaining 41 patients are evaluable. Blood was drawn at baseline, week 4, and week 24 for evaluation of virologic and immunologic parameters as well as functional ability of lymphocytes. CD4 cells and plasma HIV RNA were quantified at each evaluation.

Peripheral blood mononuclear cells (PBMCs) were stimulated with p24 antigen and PHA, a T-cell mitogen, to assess proliferative responses. Lymphocytes were evaluated for the presence of CD28, a cell-surface marker that tends to be down-regulated in patients with HIV infection. In addition, plasma levels of two of the interleukins, 12 and 10, were measured. IL-12 is associated with cellular immunity, important in fighting HIV infection; IL-10 is associated with down-regulation of this response, but the substance also inhibits HIV in vitro.

Most patients demonstrated improved proliferative PBMC responses in vitro when stimulated with PHA after treatment with protease inhibitors. Responses to p24 antigen also improved in the majority of patients, but many of these responses were transient. Angel et al. also found that the percentage of CD8 cells expressing CD28 increased from 32% to 46% with treatment; the latter percentage is similar to the levels of CD8 cells bearing this marker in persons without HIV infection. The presence of CD28 is associated with increased IL-2 production, a cellular product that plays an important role in the body's response to HIV. Furthermore, after treatment with protease inhibitors, cells from participants produced greater levels of IL-12 when exposed to a cellular stimulant. Levels of IL-10 were also increased.

Angel JB, Kumar A, Parato K, Filion LG, Diaz-Mitoma F, Daftarian P, et al. Improvement in cell-mediated immune function during potent anti-human-immunodeficiency-virus therapy with ritonavir plus saquinavir. J Infect Dis 1998; 177: 898-904.

Dr. Paul A. Volberding, the editor-in-chief of HIV Newsline, comments:

This was a short study, and no direct correlation can be drawn between any of the observed changes and the participants' clinical status. It is unclear how long these improvements in cell-mediated immunity will persist, but Angel et al. have helped elucidate early events in the natural history of cell-mediated function in patients treated with protease inhibitors. Some of these events might explain why clinicians have observed fewer opportunistic infections and other immunodeficiency-related events in HIV patients receiving this potent class of drugs.

Withdrawing secondary CMV prophylaxis

Spanish study provides some preliminary criteria

Patients who respond well to maximally suppressive antiretroviral therapy experience marked reductions in viral burden and significant increases in CD4 cell counts. Ever since these virologic and immunologic improvements were first observed in patients treated with protease-inhibitor-containing combination regimens, clinicians have been wrestling with the question of whether these responses make it possible to withdraw certain forms of prophylaxis without jeopardizing the health of their patients.

Dr. William Powderly, a member of the editorial advisory board of HIV Newsline, addressed this clinical conundrum in these pages more than two years ago, shortly after protease inhibitors became widely available (see "Prophylaxis of OIs in the Age of Protease Inhibitors: Can We Stop the Bactrim?" in Vol. 2, No. 3). This crucial question can be answered more definitively now than two years ago -- at least where certain types of patients and certain types of prophylaxis are concerned -- and Dr. Powderly will therefore provide an update on this all-important topic in the next issue of HIV Newsline.

Taking selected patients off superfluous primary and secondary prophylaxis regimens -- and halting unneeded suppressive therapies -- is attractive for many reasons. It reduces the overall cost of care, and it eliminates the likelihood of adverse reactions to the medications used in such regimens. But the greatest advantage of withdrawing unnecessary prophylaxis is that it simplifies the patient's daily dosing regimen -- and given the complexity of the multidrug regimens that are currently used to achieve maximal suppression of HIV replication, anything that reduces the total number of pills that a patient must take is likely to enhance compliance with the patient's assigned antiretroviral regimen.

With this objective in mind, a group of Spanish clinicians designed a protocol to study the clinical course of patients who terminated secondary anti-CMV prophylaxis after they had achieved an adequate response to a multidrug antiretroviral regimen that included at least one protease inhibitor. Tural et al. recruited 16 patients with AIDS and CMV retinitis. These patients had completed induction therapy with ganciclovir or foscarnet and were receiving maintenance therapy. They were started on antiretroviral regimens that contained two nucleoside analogs and at least one protease inhibitor (ritonavir, ritonavir/saquinavir, or indinavir). All 16 subjects had previously been on dual-nucleoside therapy; three of them dropped out of the study because they were unable to adhere to combination therapy.

Only patients who met certain criteria for positive response were candidates for termination of CMV prophylaxis. These criteria included a CD4 count greater than 150 cells/mm3 and HIV RNA levels less than 200 copies/mL after three months of combination therapy. Three of the remaining 13 patients did not meet these immunologic and virologic criteria, and three patients who did meet the criteria decided not to interrupt their CMV prophylaxis. Tural et al. reported results on the seven patients who actually stopped taking their anti-CMV medications.

Baseline characteristics for this small cohort included a median CD4 count of 35 cells/mm3 and a median viral load of greater than 125,000 copies/mL. The seven subjects had received secondary CMV prophylaxis for a median of 11 months (range: 3-16 months). While receiving maintenance therapy, none of the patients had a recurrence of CMV retinitis, although one patient did develop biopsy-proven CMV colitis.

Secondary prophylaxis was withdrawn, and over the next nine months there were no new episodes of CMV retinitis or other AIDS-defining events among these seven patients. CD4 counts, HIV RNA, and qualitative CMV PCR levels were monitored throughout the trial. In addition, subjects received ophthalmologic evaluations weekly for the first month after prophylaxis was withdrawn, and monthly evaluations thereafter.

Tural et al. do not claim to have written a definitive chapter on the cessation of anti-CMV therapy in patients with retinitis who respond well to maximally suppressive antiretroviral therapy, but they feel confident that the participants in this study will not need future treatment for this infection.

Tural C, Romeu J, Sirera G, Andreu D, Conejero M, Ruiz S, et al. Long-lasting remission of cytomegalovirus retinitis without maintenance therapy in human immunodeficiency virus-infected patients. J Infect Dis 1998; 177: 1080-83.

Dr. Judith A. Aberg, a member of the editorial advisory board of HIV Newsline, comments:

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 was seldom if ever possible, recurrence was inevitable, and the eventual failure of all known treatments was to be anticipated.

In the February 1998 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, page 16). 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 this one 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 that therapy.

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 such a study 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.

Two promising new treatments for anal warts

Topical treatments may eliminate the need for chemical or surgical ablation

The viruses that cause warts are expert at finding places to call home. In addition to fingers and toes, favored sites include the epithelium of the anal canal, the external anal area, and the genitals. Researchers have identified more than 100 members of the family of wart-causing viruses known as human papilloma viruses (HPVs). Individuals with compromised immune systems are prey to all of these viruses, including the subtypes of HPV that are associated with cancerous tumors.

Anogenital warts are disproportionately prevalent among people with HIV disease. These warts can be especially recalcitrant in the immunocompromised host, and regular ablative therapy is often necessary. Care providers will therefore welcome the results of two recently published studies that used new topical treatments for anogenital warts. Although the studies did not specifically include HIV-infected participants, one of the investigators has indicated that imiquimod cream does yield good results when used in HIV-infected patients (personal communication).

Imiquimod cream is a novel treatment for anogenital warts. The exact mechanism of action is unknown, but imiquimod is believed to induce local production of interferon alpha, among other cytokines. (Interferon alpha itself is sometimes used to treat HPV warts.) Edwards et al. recruited 311 men and women with external anogenital warts, ranging in number from 2 to 50 lesions. Patients were randomized to 5% imiquimod cream, 1% imiquimod cream, or a placebo cream. The regimen involved thrice-weekly application at night for 16 weeks. The most common adverse reaction was local erythema. Four patients dropped out of the study because of side effects.

According to an intent-to-treat analysis, total wart clearance was achieved in 50% of those randomized to 5% cream, 21% of those receiving 1% cream, and 11% of those receiving the placebo, indicating that a certain amount of spontaneous resolution does occur. Among recipients of 5% cream, an additional 81% experienced partial clearance (which in this study meant that more than half of the patient's warts were eradicated). Higher percentages of women experienced complete clearance in all three treatment arms. Of patients on the higher dosage who experienced total clearance of warts, 13% eventually had a recurrence of at least one wart.

In a contemporaneous article in Archives of Dermatology, Tyring et al. report on a novel formulation for treating HPV warts. Podofilox is a compound with activity against HPV that has been produced in a topical resin formulation. In this study, 0.5% topical gel was evaluated against a placebo gel in 326 patients with anogenital, perianal, and external genital warts. The treatment regimen was twice-daily application for three consecutive days, followed by four days without treatment.

Treatment ranged from 9 to 16 weeks. Complete clearance was achieved by 62/167 (37.1%) patients receiving the active drug as compared to 2/86 (2.3%) receiving the placebo. Clearance was more frequent for anogenital and external genital warts than for perianal warts.

The adverse events that occurred with significantly greater frequency in the treatment arm were burning, inflammation, itching, erosion, pain, and bleeding. Recurrence, which was defined as at least one wart within 12 weeks of the completion of therapy, was noted in 30.9% of the patients who were successfully treated with podofilox gel.

Edwards L, Ferenczy A, Eron L, Baker D, Owens ML, Fox TL, et al. Self-administered topical 5% imiquimod cream for external anogenital warts. Arch Dermatol 1998; 134: 25-30.

Tyring S, Edwards L, Cherry LK, Ramsdell WM, Kotner S, Greenberg MD, et al. Safety and efficacy of 0.5% podofilox gel in the treatment of anogenital warts. Arch Dermatol 1998; 134: 33-38.

Human papilloma virus and anal cancer

More evidence of an association, especially in HIV-positive men with persistent infection

The family of viruses that causes warts can also cause more serious lesions in the anogenital areas. Although confirmatory data are lacking, there is strong suspicion that some of these anal lesions are precursors to anal cancer. Certain cervical lesions caused by human papilloma virus (HPV) are known to progress to cervical cancer, making aggressive treatment of these lesions imperative. Obviously, it would be useful to determine if there is a similar association between high-grade anal HPV lesions and anal cancer.

Palefsky et al. set out to compare the incidence of high-grade squamous intraepithelial anal lesions in HIV-positive and seronegative homosexual and bisexual men. The cohort was recruited entirely in San Francisco between 1991 and 1994 and followed for four years. A total of 277 HIV-positive men and 221 HIV-negative men participated.

In this study, non-cancerous anal HPV lesions were evaluated by cytology and histology. Cytologic results were classified as benign, atypical squamous cells of unknown significance (ASCUS), low-grade squamous intraepithelial lesions (LSIL), and high-grade squamous intraepithelial lesions (HSIL). Histologic results were the same, excluding the ASCUS classification. Over the observation period, 37% of the HIV-positive men and 17% of the HIV-negative men developed HSIL. Among those developing HSIL, large percentages of the subjects had lower-grade lesions at baseline, regardless of HIV status, lending further support to the theory that the various classifications of lesions represent a spectrum of progression.

Factors associated with development of HSIL included a higher number of lesions (in both HIV-positive and seronegative men), persistent versus intermittent infection, HIV infection, lower CD4 counts (<200 cells) among those with HIV, and the presence of more oncogenic subtypes of HPV (Group B RLU). Interestingly, both the presence of hemorrhoids and the recreational use of marijuana were associated with a lower incidence of HSIL. More frequent episodes of receptive anal intercourse were not associated with development of HSIL.

The epidemiology and pathophysiology of non-cancerous HPV-associated anal lesions need further study. If the natural history of HPV-associated anal lesions can be better characterized, there may be greater justification for screening for, and aggressive treatment of, these lesions. This information is especially important for clinicians who treat HIV-infected patients, since the prevalence of these lesions appears to be much higher in this group compared with the general population.

Palefsky JM, Holly EA, Ralston ML, Jay N, Berry M, Darragh TM. High incidence of anal high-grade squamous intra-epithelial lesions among HIV-positive and HIV-negative homosexual and bisexual men. AIDS 1998; 12: 495-503.

Dramatic decreases in HIV prevalence among Thai military conscripts

Proof of the effectiveness of a vast national education campaign

More evidence from abroad shows that aggressive, explicit, and regularly reinforced public-health campaigns can modulate risky sexual behavior. In Thailand, the government has funded a vast education program called the "100% Condom Program" -- a no-nonsense title for a no-nonsense campaign. The primary purpose of this program is to decrease the spread of HIV. New evidence shows that this program not only works, it has an ancillary benefit: rates of other sexually transmitted diseases have plunged in studied populations.

A collaborative effort by researchers at Johns Hopkins School of Hygiene and Public Health, Kawila Hospital, the Thai Army Medical Corps, and Chiang Mai University examined trends in HIV and STD prevalence among Thai men inducted into the Thai army between 1991 and 1993. Two cohorts were followed. The first consisted of 2,417 men who were conscripted in 1991 and seen at six-month intervals for two years; the second comprised 1,669 recruits who were followed for 18 months. Celentano et al. endeavored to find differences over time that might be linked to the launching of the 100% Condom Program.

The HIV prevalence in both cohorts at baseline was an astonishingly high 12%. However, the incidence rates over time were dramatically different. In the first cohort, followed from 1991 to 1993, the incidence of new HIV infections was 2.48 per 100 person-years. This compared with a rate of only 0.55 per 100 person-years in the cohort recruited after the launch of this ambitious prevention program. These encouraging results were matched by significant reductions in the overall rates of new STDs, from 17 per 100 person-years in the first group to 1.8 per 100 person-years in the second. Specific infections that dropped in incidence included syphilis (9-fold decrease), gonorrhea (10-fold), non-gonococcal urethritis (five-fold), and chancroid (16-fold).

The principal behavioral changes that appear to be associated with the decreased HIV and STD incidence were reduced visits to brothels and consistent use of condoms. Since overall HIV prevalence rates among female sex workers remained stable (at approximately 45%) during both periods of study, the authors postulate that behavioral changes, rather than reduced exposure to infection, explain the downward trend of HIV transmission among males aged 19 to 23. Another interesting revelation was that men who visited brothels alone were more likely to engage in risky behavior. The authors report that HIV prevalence rates among conscripted Thai men have continued to trend downward, from 6.6% in 1995 to 4.7% in 1996 and 4.4% in 1997.

Celentano DD, Nelson KE, Lyles CM, Beyrer C, Eiumtrakul S, Go VFL, et al. Decreasing incidence of HIV and sexually transmitted diseases in young Thai men: Evidence for success of the HIV/AIDS control and prevention program. AIDS 1998; 12: F29-F36.

Something More You Need to Know About Viagra
Diminished libido is a problem for many seropositive individuals, 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.

All HIV-positive men who take Viagra should be cautioned against using amyl nitrate or butyl nitrate, more commonly known as "poppers," concurrently with Viagra. In the clinical setting, these nitrates are used to diagnose heart disease. In slightly 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.

Better Treatment for CMV Retinitis: An Update
In the February 1998 issue of AIDS Care, Dr. Mark Jacobson described the newest strategies to slow disease progression in patients afflicted with cytomegalovirus retinitis, once a common complication of late-stage HIV infection. Care providers who treat patients with advanced HIV disease are seeing much less CMV retinitis today than they saw before the widespread adoption of protease-inhibitor-containing combination antiretroviral therapies, but this OI remains a potentially serious threat to AIDS patients.

An advisory committee to the F.D.A. has just recommended approval of a new technology for treating CMV retinitis. Developed by Isis Pharmaceuticals, fomivirsen (Vitravene®) is the first antisense compound to win tentative F.D.A. approval. Unlike the standard treatments for CMV retinitis, all of them toxic, this agent works by blocking the genes that govern CMV replication -- a mode of action that has markedly fewer side effects than older therapies. Fomivirsen is injected directly into affected eyes. Some patients given the drug experience a temporary increase in intraocular pressure and mild-to-moderate inner-eye inflammation, but these side effects generally resolve promptly and without lasting effects.

Given the dramatic decrease in all OIs, CMV included, that we have seen since the advent of protease-inhibitor-containing therapies, the real significance of fomivirsen's approval may be as a harbinger of the arrival of the antisense compounds, with their unique combination of high potency and low toxicity.

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This article was provided by San Francisco General Hospital. It is a part of the publication HIV Newsline.