Donald I. Abrams

Non-Hodgkin's lymphoma in 90 homosexual men: relation to generalized lymphadenopathy and the acquired immunodeficiency syndrome

We describe the histologic and clinical features of non-Hodgkins lymphoma diagnosed between January 1980 and December 1983 in 90 homosexual men from San Francisco, Los Angeles, Houston, and New York. The median age was 37 years, with an age distribution identical to that for cases of AIDS reported to the Centers for Disease Control. Sixty-two per cent of the patients had high-grade (aggressive) subtypes of lymphoma, 29 per cent had subtypes of intermediate grade, and 7 per cent had low-grade subtypes. Histologic subtypes and malignant cell phenotypes were consistent with a B-cell origin. All but two men had extranodal lymphoma: central-nervous-system, bone-marrow, bowel, and mucocutaneous sites were most commonly involved. Thirty-five of 66 evaluable men (53 per cent) had complete responses to combination chemotherapy or radiotherapy or both, and thus far, 19 (54 per cent) of them have had a relapse. Mortality and morbidity were closely related to prodromal manifestations; death or illness have occurred in 19 (91 per cent) of the 21 men who presented with AIDS, in 26 (79 per cent) of the 33 who presented with generalized lymphadenopathy, and in 5 (42 per cent) of the 12 who had no prodromal manifestations. Mortality rates analyzed according to histologic grade were higher than currently reported rates in other patient populations. Kaposis sarcoma or severe opportunistic infections characteristic of AIDS developed in 14 of 33 men (42 per cent) who presented with generalized lymphadenopathy and in 3 of 12 (33 per cent) without prodromal manifestations. We conclude that non-Hodgkins lymphoma in members of an AIDS risk group is a serious manifestation of AIDS and the AIDS-related complex.

A randomized study of antiretroviral management based on plasma genotypic antiretroviral resistance testing in patients failing therapy

ObjectiveTo determine the short-term effects of using genotypic antiretroviral resistance testing (GART) with expert advice in the management of patients failing on a protease inhibitor and two nucleoside reverse transcriptase inhibitors. DesignProspective randomized controlled trial. SettingMulticenter community-based clinical trials network. PatientsOne-hundred and fifty-three HIV-infected adults with a threefold or greater rise in plasma HIV-1 RNA on at least 16 weeks of combination antiretroviral therapy. InterventionsRandomization was either to a GART group, where genotype interpretation and suggested regimens were provided to clinicians, or to a no-GART group, where treatment choices were made without such input. Main outcomes measuresPlasma HIV-1 RNA levels and CD4 cell counts were measured at 4, 8, and 12 weeks following randomization. The primary endpoint was change in HIV-1 RNA levels from baseline to the average of the 4 and 8 week levels. ResultsThe average baseline CD4 cell count was 230 × 106 cells/l and the median HIV-1 RNA was 28 085 copies/ml. At entry, 82 patients were failing on regimens containing indinavir, 51 on nelfinavir, 11 on ritonavir, and nine on saquinavir. HIV-1 RNA, averaged at 4 and 8 weeks, decreased by 1.19 log10 for the 78 GART patients and -0.61 log10 for the 75 no-GART patients (treatment difference: −0.53 log, 95% confidence interval, −0.77 to −0.29;P  = 0.00001). Overall, the best virologic responses occurred in patients who received three or more drugs to which their HIV-1 appeared to be susceptible. ConclusionIn patients failing triple drug therapy, GART with expert advice was superior to no-GART as measured by short-term viral load responses.

Cannabis in painful HIV-associated sensory neuropathy A randomized placebo-controlled trial

Objective: To determine the effect of smoked cannabis on the neuropathic pain of HIV-associated sensory neuropathy and an experimental pain model. Methods: Prospective randomized placebo-controlled trial conducted in the inpatient General Clinical Research Center between May 2003 and May 2005 involving adults with painful HIV-associated sensory neuropathy. Patients were randomly assigned to smoke either cannabis (3.56% tetrahydrocannabinol) or identical placebo cigarettes with the cannabinoids extracted three times daily for 5 days. Primary outcome measures included ratings of chronic pain and the percentage achieving >30% reduction in pain intensity. Acute analgesic and anti-hyperalgesic effects of smoked cannabis were assessed using a cutaneous heat stimulation procedure and the heat/capsaicin sensitization model. Results: Fifty patients completed the entire trial. Smoked cannabis reduced daily pain by 34% (median reduction; IQR = −71, −16) vs 17% (IQR = −29, 8) with placebo (p = 0.03). Greater than 30% reduction in pain was reported by 52% in the cannabis group and by 24% in the placebo group (p = 0.04). The first cannabis cigarette reduced chronic pain by a median of 72% vs 15% with placebo (p < 0.001). Cannabis reduced experimentally induced hyperalgesia to both brush and von Frey hair stimuli (p ≤ 0.05) but appeared to have little effect on the painfulness of noxious heat stimulation. No serious adverse events were reported. Conclusion: Smoked cannabis was well tolerated and effectively relieved chronic neuropathic pain from HIV-associated sensory neuropathy. The findings are comparable to oral drugs used for chronic neuropathic pain.

Interleukin-2 therapy in patients with HIV infection.

BACKGROUND Used in combination with antiretroviral therapy, subcutaneous recombinant interleukin-2 raises CD4+ cell counts more than does antiretroviral therapy alone. The clinical implication of these increases is not known. METHODS We conducted two trials: the Subcutaneous Recombinant, Human Interleukin-2 in HIV-Infected Patients with Low CD4+ Counts under Active Antiretroviral Therapy (SILCAAT) study and the Evaluation of Subcutaneous Proleukin in a Randomized International Trial (ESPRIT). In each, patients infected with the human immunodeficiency virus (HIV) who had CD4+ cell counts of either 50 to 299 per cubic millimeter (SILCAAT) or 300 or more per cubic millimeter (ESPRIT) were randomly assigned to receive interleukin-2 plus antiretroviral therapy or antiretroviral therapy alone. The interleukin-2 regimen consisted of cycles of 5 consecutive days each, administered at 8-week intervals. The SILCAAT study involved six cycles and a dose of 4.5 million IU of interleukin-2 twice daily; ESPRIT involved three cycles and a dose of 7.5 million IU twice daily. Additional cycles were recommended to maintain the CD4+ cell count above predefined target levels. The primary end point of both studies was opportunistic disease or death from any cause. RESULTS In the SILCAAT study, 1695 patients (849 receiving interleukin-2 plus antiretroviral therapy and 846 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 202 cells per cubic millimeter were enrolled; in ESPRIT, 4111 patients (2071 receiving interleukin-2 plus antiretroviral therapy and 2040 receiving antiretroviral therapy alone) who had a median CD4+ cell count of 457 cells per cubic millimeter were enrolled. Over a median follow-up period of 7 to 8 years, the CD4+ cell count was higher in the interleukin-2 group than in the group receiving antiretroviral therapy alone--by 53 and 159 cells per cubic millimeter, on average, in the SILCAAT study and ESPRIT, respectively. Hazard ratios for opportunistic disease or death from any cause with interleukin-2 plus antiretroviral therapy (vs. antiretroviral therapy alone) were 0.91 (95% confidence interval [CI], 0.70 to 1.18; P=0.47) in the SILCAAT study and 0.94 (95% CI, 0.75 to 1.16; P=0.55) in ESPRIT. The hazard ratios for death from any cause and for grade 4 clinical events were 1.06 (P=0.73) and 1.10 (P=0.35), respectively, in the SILCAAT study and 0.90 (P=0.42) and 1.23 (P=0.003), respectively, in ESPRIT. CONCLUSIONS Despite a substantial and sustained increase in the CD4+ cell count, as compared with antiretroviral therapy alone, interleukin-2 plus antiretroviral therapy yielded no clinical benefit in either study. (ClinicalTrials.gov numbers, NCT00004978 [ESPRIT] and NCT00013611 [SILCAAT study].)

Cd4+ count and risk of non-aids diseases following initial treatment for Hiv infection

Background:Reductions in AIDS-related morbidity and mortality following the advent of combination antiretroviral therapy have coincided with relative increases in chronic non-AIDS end-organ diseases among HIV+ patients. Objective:To examine the association of latest CD4+ counts with risk of non-AIDS diseases in a cohort of 1397 patients who initiate antiretroviral therapy. Methods:CD4+ counts and HIV RNA levels along with fatal, and non-fatal, AIDS and non-AIDS diseases (liver, cardiovascular, renal, and cancer) were assessed over a median follow-up of 5 years. Cox proportional regression models were used to study risk associations. Results:A total of 227 patients experienced an AIDS event and 80 patients developed a non-AIDS disease event. Both AIDS and non-AIDS diseases rates (events/100 person-years), respectively, declined with higher latest CD4+ counts: 13.8 and 2.1 with latest CD4+ counts less than 200 cells/μl; 2.0 and 1.7 for counts of 200–350 cells/μl; and 0.7 and 0.7 for counts greater than 350 cells/μl. After adjusting for baseline covariates and the latest HIV RNA level, risk of AIDS and non-AIDS diseases were lowered by 44% (95% confidence interval for hazard ratio 0.50–0.62, P < 0.01) and 14% (95% confidence interval for hazard ratio 0.77–0.96, P = 0.01), respectively, for each 100 cell/μl higher latest CD4+ count. Conclusion:Higher CD4+ counts on antiretroviral therapy are associated with lower rates of non-AIDS diseases and AIDS. These findings expand our understanding of the implications of HIV-related immunodeficiency and motivate randomized studies to evaluate the effects of antiretroviral therapy on a broad set of clinical outcomes at CD4+ counts greater than 350 cells/μl.

Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapy

Objective: To determine the extent to which HIV-infected patients, including those with advanced immunodeficiency, can reverse peripheral CD4 T-cell depletion while maintaining long-term viral suppression on highly active antiretroviral therapy. Design: Cohort study. Participants: Four-hundred and twenty-three HIV-infected patients who initiated HAART prior to 1998 and achieved a viral load ⩽ 1000 copies/ml by 48 weeks were evaluated for up to 4 years or until plasma HIV RNA levels increased to > 1000 copies/ml. Main outcome measure: CD4 count changes. Results: Among patients who maintained plasma HIV RNA levels ⩽ 1000 copies/ml, CD4 counts continued to increase through year 4 of HAART. In the last year examined, from year 3 to 4 of HAART, mean CD4 count gains were +89 × 106, +86 × 106, +95 × 106, and +88 × 106/l in patients with pre-therapy CD4 counts of < 50 × 106, 50 × 106–199 × 106, 200 × 106–349 × 106, and ⩾ 350 × 106/l, respectively (all gains were significantly greater than zero; P < 0.05). Among those with a pre-therapy CD4 count of < 50 × 106/l, 88% achieved a CD4 cell count of ⩾ 200 × 106/l and 59% achieved a count of ⩾ 350 × 106/l by year 4. Factors associated with increased CD4 cell count gains from month 3 to year 4 included lower pre-therapy CD4 cell count, younger age, female sex, and infrequent low-level viremia (versus sustained undetectable viremia). Conclusions: Most patients who achieve and maintain viral suppression on HAART continue to experience CD4 T-cell gains through 4 years of therapy. The immune systems capacity for CD4 T lymphocyte restoration is not limited by low pre-therapy CD4 counts.

Weight loss as a predictor of survival and disease progression in HIV infection

Severe weight loss in HIV is associated with decreased length of survival. It is unclear whether mild weight loss is associated with an increased risk of death or opportunistic complications of HIV. Participants in four interventional studies (n = 2382) conducted by a community-based clinical trials network were evaluated for percentage change in weight during their first 4 months in the study. Proportional hazards models were performed for the occurrence of opportunistic complications and death subsequent to the 4-month visit. The relative risk of death and opportunistic complications for those with 5% to 10% weight loss over 4 months was 2.22 (p < .001) and 1.89 (p < .001), respectively, and 1.26 (p < .01) and 1.19 (p < .01) among those who lost 0% to 5% of their body weight, respectively, when compared with those with no weight loss. Among those who lost 5% to 10% of their body weight, the relative risk of individual opportunistic complications increased significantly, including Pneumocystis carinii pneumonia (PCP) (1.61; p < .01), cytomegalovirus (CMV) (2.33; p < .001), and Mycobacterium avium complex (MAC) (1.81; p < .01). As little as 5%t weight loss over a 4-month period is associated with increased risk of death and opportunistic complications in HIV. A weight loss of 5% to 10% is also associated with an increased risk of individual opportunistic complications.

HIV INFECTION AND THE RISK OF CANCERS WITH AND WITHOUT A KNOWN INFECTIOUS CAUSE

Objective:To evaluate the risk of cancers with and without a known infectious cause in HIV-infected persons. Design:Retrospective cohort study. Methods:Adult HIV-infected and matched HIV-uninfected members of Kaiser Permanente followed between 1996 and 2007 for incident AIDS-defining cancers (ADCs), infection-related non-AIDS-defining cancers (NADCs; anal squamous cell, vagina/vulva, Hodgkins lymphoma, penis, liver, human papillomavirus-related oral cavity/pharynx, stomach) and infection-unrelated NADC (all other NADCs). Results:We identified 20 277 HIV-infected and 202 313 HIV-uninfected persons. HIV-infected persons experienced 552 ADC, 221 infection-related NADC, and 388 infection-unrelated NADC. HIV-uninfected persons experienced 179 ADC, 284 infection-related NADC, and 3418 infection-unrelated NADC. The rate ratio comparing HIV-infected and HIV-uninfected persons for ADC was 37.7 [95% confidence interval (CI): 31.7–44.8], with decreases in the rate ratio over time (P < 0.001). The rate ratio for infection-related NADC was 9.2 (95% CI: 7.7–11.1), also with decreases in the rate ratio over time (P < 0.001). These results were largely influenced by anal squamous cell cancer and Hodgkins lymphoma. The rate ratio for infection-unrelated NADC was 1.3 (95% CI: 1.2–1.4), with no change in the rate ratio over time (P = 0.44). Among infection-unrelated NADCs, other anal, skin, other head and neck, and lung cancer rates were higher and prostate cancer rates lower in HIV-infected persons. Among all infection-unrelated NADCs, the rate ratio decreased over time only for lung cancer (P = 0.007). Conclusion:In comparison with those without HIV infection, HIV-infected persons are at particular risk for cancers with a known infectious cause, although the higher risk has decreased in the antiretroviral therapy era. Cancers without a known infectious cause are modestly increased in HIV-infected persons compared with HIV-uninfected persons.

HIV-induced immunodeficiency and mortality from AIDS-defining and non-AIDS-defining malignancies

Objective:To evaluate deaths from AIDS-defining malignancies (ADM) and non-AIDS-defining malignancies (nADM) in the D:A:D Study and to investigate the relationship between these deaths and immunodeficiency. Design:Observational cohort study. Methods:Patients (23 437) were followed prospectively for 104 921 person-years. We used Poisson regression models to identify factors independently associated with deaths from ADM and nADM. Analyses of factors associated with mortality due to nADM were repeated after excluding nADM known to be associated with a specific risk factor. Results:Three hundred five patients died due to a malignancy, 298 prior to the cutoff for this analysis (ADM: n = 110; nADM: n = 188). The mortality rate due to ADM decreased from 20.1/1000 person-years of follow-up [95% confidence interval (CI) 14.4, 25.9] when the most recent CD4 cell count was <50 cells/μl to 0.1 (0.03, 0.3)/1000 person-years of follow-up when the CD4 cell count was more than 500 cells/μl; the mortality rate from nADM decreased from 6.0 (95% CI 3.3, 10.1) to 0.6 (0.4, 0.8) per 1000 person-years of follow-up between these two CD4 cell count strata. In multivariable regression analyses, a two-fold higher latest CD4 cell count was associated with a halving of the risk of ADM mortality. Other predictors of an increased risk of ADM mortality were homosexual risk group, older age, a previous (non-malignancy) AIDS diagnosis and earlier calendar years. Predictors of an increased risk of nADM mortality included lower CD4 cell count, older age, current/ex-smoking status, longer cumulative exposure to combination antiretroviral therapy, active hepatitis B infection and earlier calendar year. Conclusion:The severity of immunosuppression is predictive of death from both ADM and nADM in HIV-infected populations.

Target platelet antigen in homosexual men with immune thrombocytopenia.

A syndrome of isolated immune thrombocytopenic purpura (ITP) has recently been described in homosexual men. We have identified an antiplatelet antibody in the serum of 29 of 30 homosexual men with isolated ITP. The antibody binds to a platelet membrane antigen of 25,000 daltons, and binding is effected by the F(ab)2 portion of the immunoglobulin. Similar antibody activity was not detected in serum from 30 nonhomosexual patients with either ITP or nonimmune thrombocytopenia. The 25,000-dalton antigen was not found on other hematopoietic cells, and it was distinct from the core protein of the AIDS-associated retrovirus. In contrast, serum antibody reacted with a 25,000-dalton antigen associated with cultured herpes simplex virus Types I and II. In these experiments the antigen appeared to be derived from green-monkey kidney cells in which the herpes simplex viruses were grown. Identical antigenic activity was also demonstrated in uninfected human skin fibroblasts. We conclude that ITP in homosexual men is accompanied by a serum antibody directed against a platelet antigen of 25,000 daltons. The nature of the antigen and the relation of the serum antibody to ITP require further study.