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Surrogate markers for assessing treatment response in HIV disease.

OBJECTIVE: To provide an awareness of the issues surrounding the selection and utility of surrogate markers to evaluate treatment response for new antiretroviral therapies for HIV infection. DATA SOURCES: A MEDLINE search of applicable articles published between 1987 to the present, including clinical trials, commentaries, and editorials, was performed. DATA SYNTHESIS: Surrogate markers are proximal indicators that are predictive of rare or distant outcomes and can be used in clinical trials to decrease sample size and study duration. Characteristics of potential surrogate endpoints include relevance to disease state, face validity, ability to be detected in the majority of patients, and correlation between treatment-induced changes and terminal endpoints. Potential surrogate markers for assessing treatment response in HIV infection can be categorized as either virologic (p24 antigen, plasma viremia, proviral DNA) or immunologic (CD4+ lymphocytes, neopterin, beta 2-microglobulin, soluble interleukin-2 receptors, immunoglobulin A [IgA]). The CD4+ lymphocyte count and the p24 antigen have been evaluated in most of the clinical trials examining antiretroviral agents and have the greatest documentation supporting their use. Neopterin and beta 2-microglobulin are nonspecific markers, but may improve the predictive value of the CD4+ count when used in combination. Other markers (i.e., soluble interleukin-2 receptors, IgA) remain relatively unstudied at this point. CONCLUSIONS: There is no current consensus regarding the selection of surrogate markers for HIV disease. On the basis of the present literature, the CD4+ lymphocyte count has the greatest endorsement: however, combination with several surrogate markers may prove to be useful in clinical trials. Studies are needed to verify the reliability of surrogate markers used alone and in combination to predict therapeutic response from antiretroviral therapy.

Biomarkers↗

International Travel: Recommendations for the HIV-infected Patient.

In order to prevent travel-related diseases in patients infected with HIV, pretravel planning that includes vaccination, chemoprophylaxis, and behavioral modification is recommended. Many HIV-infected individuals successfully treated with highly active antiretroviral therapy may travel safely. However, patients with reduced CD4 lymphocyte counts are at increased risk for bacterial, mycobacterial, viral, fungal, and parasitic infections. Recommendations for vaccination and chemoprophylaxis are based on immune status and risk of infection. The efficacy of vaccination is dependant on CD4 lymphocyte count; inactivated and polysaccharide vaccines are considered safe in this population. Behavioral modifications to prevent food- and waterborne disease are an important component of disease prevention. A travel-health practitioner should review travel duration, destination, and activities, and assess the risk-benefit ratio of vaccination and chemoprophylaxis, in order to reduce the likelihood of travel-associated illness.

Journal Article↗

Mycobacterial and nonbacterial pulmonary complications in hospitalized patients with human immunodeficiency virus infection: a prospective, cohort study.

BACKGROUND: A prospective observational study was done to describe nonbacterial pulmonary complications in hospitalized patients with human immunodeficiency virus (HIV) infection. METHODS: The study included 1,225 consecutive hospital admissions of 599 HIV-infected patients treated from April 1995 through March 1998. Data included demographics, risk factors for HIV infection, Acute Physiology and Chronic Health Evaluation (APACHE) II score, pulmonary complications, CD4+ lymphocyte count, hospital stay and case-fatality rate. RESULTS: Patient age (mean +/- SD) was 38.2 +/- 8.9 years, 62% were men, and 84% were African American. The median APACHE II score was 14, and median CD4+ lymphocyte count was 60/microL. Pulmonary complications were Pneumocystis carinii pneumonia (85) in 78 patients, Mycobacterium avium complex (51) in 38, Mycobacterium tuberculosis (40) in 35, Mycobacterium gordonae (11) in 11, Mycobacterium kansasii (10) in 9, Cytomegalovirus (10) in 10, Nocardia asteroides (3) in 3, fungus ball (2) in 2, respiratory syncytial virus (1), herpes simplex virus (1), Histoplasma capsulatum (1), lymphoma (3) in 3, bronchogenic carcinoma (2) in 2, and Kaposi sarcoma (1). The case-fatality rate of patients was 11% with Pneumocystis carinii pneumonia; 5%, Mycobacterium tuberculosis; 6%, Mycobacterium avium complex; and 7%, noninfectious pulmonary complications. CONCLUSION: Most pulmonary complications in hospitalized patients with HIV are from Pneumocystis and mycobacterial infection.

Journal Article↗

Beta-2-microglobulin, neopterin and monocyte Fc gamma receptors in opportunistic infections of HIV-positive patients.

The aim of this study was to examine serum and cellular markers of immune activation in HIV-positive (HIV+) patients with and without current opportunistic infections. Fc gamma receptor (Fc gamma R) expression on monocytes, serum neopterin and beta-2-microglobulin were studied. Thirty HIV+ patients (grouped according to Centers for Disease Control (CDC) classification) were studied and compared with 27 normal blood donor controls. HIV+ patients were further separated into three groups: 2 (CDC II), 3 (CDC III/IV without infections) and 4 (CDC III/IV with current infections). Eleven of the patients had current opportunistic infections. Results indicate that beta-microglobulin, neopterin, fc gamma RI, Fc gamma RII and Fc gamma III were significantly increased in HIV+ patients compared to controls. Further analysis of the data using Tukey-Kramer all pairwise comparison revealed that for beta-2-microglobulin the mean values for patients in groups 2, 3 and 4 were significantly different (P < 0.0001). Serum neopterin levels and the percentage of CD14+14+ monocytes expressing Fc gamma RIII showed significant differences in the mean values of group 2 and group 4; similarly, for CD4+ lymphocyte counts group 2 and group 4 were significantly different. These results indicated that beta-2-microglobulin, neopterin and CD14+ monocyte Fc gamma RIII are increased particularly in HIV+ patients with current opportunistic infections while CD4+ lymphocyte counts are reduced. The results suggest that these markers, particularly beta-2-microglobulin, could be useful indicators of the inflammatory process associated with opportunistic infection at later stages of disease where other laboratory markers may be atypical.

AIDS-Related Opportunistic Infections↗

[Withdrawal of Pneumocystis carinii pneumonia prophylaxis in patients receiving efficacious combined antiretroviral treatment. Study of 85 cases].

OBJECTIVES: To analyse the incidence of Pneumocystis carinii pneumonia after the withdrawal of prophylaxis, in patients with AIDS who were receiving HAART (highly active antiretroviral treatment). PATIENTS AND METHODS: Prospective opened study of 85 patients with AIDS (CD4 lymphocytes < 200 x 10(6)/l) and whose CD4 counts had increased over 200 x 10(6)/l after HAART, 79 were under primary prophylaxis and six secondary. RESULTS: Mean CD4 lymphocytes count at the time of withdrawal was 343 x 10(6)/l. Mean time of follow-up after withdrawal was 358 days (range: 93-1,487; median: 302). None of the patients have had Pneumocystis carinii or toxoplasmosis after withdrawal of prophylaxis. CONCLUSIONS: Pneumocystis carinii prophylaxis in AIDS patients might be safety withdrawn after effective HAART.

AIDS-Related Opportunistic Infections↗

Recent infection with human immunodeficiency virus and possible rapid loss of CD4 T lymphocytes.

To assess a hypothesized trend that persons recently infected with the human immunodeficiency virus (HIV) may have more rapid declines in absolute CD4 T-lymphocyte (CD4+ cell) counts than those who were HIV-infected in earlier years, sequential CD4+ cell counts in three groups who had definable dates of HIV seroconversion between 1978 and 1992 were reviewed. The CD4+ cell counts examined were from some of the longest extant studies in the United States: 100 homosexual and bisexual men engaged in ongoing observational cohort studies in San Francisco, Denver, and Chicago since 1978 (Group 1); 89 persons in South Carolina infected after 1986 (Group 2); and 155 injecting drug users participating in an observational cohort study in Baltimore since 1988 (Group 3). For all groups, individually and in the aggregate, mean CD4+ cell counts declined rapidly in the first year after HIV infection and then stabilized. However, there was no clear trend for lower (or higher) CD4+ cell counts by fixed time after HIV seroconversion among those seroconverting in recent compared with earlier calendar years. These data do not support a hypothesized trend for more rapid loss of CD4 T lymphocytes--and, by implication, more pathogenic strains of HIV-1--among persons acquiring HIV infection in recent years.

CD4 Lymphocyte Count↗

Long-term safety and efficacy of zidovudine in patients with advanced human immunodeficiency virus disease. Zidovudine Epidemiology Study Group.

An epidemiologic study was initiated in 1987 to evaluate the long-term safety and efficacy of zidovudine in patients with advanced human immunodeficiency virus disease. Data from 886 patients with the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex and CD4+ lymphocyte count less than 0.25 x 10(9)/L are reported. Eighteen-month survival was 67% for the cohort. Pretreatment factors associated with increased survival time included index diagnosis of AIDS-related complex, hematocrit of 0.35 or greater, CD4+ lymphocyte count of 0.15 x 10(9)/L or greater, high functional status, and time from diagnosis of AIDS to treatment of less than 60 days. By proportional hazards analysis, development of serious anemia was the most significant factor associated with early death. Receiving zidovudine for a high proportion of time significantly improved chances of survival even if anemia developed. Serious leukopenia occurring in 37% and serious anemia occurring in 32% of patients. Nonhematologic adverse events were uncommon and no previously unreported adverse events were seen.

Adult↗

The effects of immune status and race on health service use among people with HIV disease.

OBJECTIVES: The purpose of this study was to examine the relationship between CD4 lymphocyte count and health service use, and to determine whether differences in the rates of service use between Whites and people of color could be identified. METHODS: Medical records for 571 HIV-infected individuals were analyzed. Incidence rates and relative rates across CD4 strata (defined by cell counts) were calculated for inpatient and outpatient events. Rate ratios comparing people of color with Whites were estimated within strata, adjusting for confounding factors using a Mantel-Haenszel pooling procedure. RESULTS: Both inpatient and outpatient service use increased over progressively lower levels of CD4 counts. Within each CD4 stratum and controlling for other factors, White participants had more HIV clinic visits and fewer admissions than people of color. Among participants with fewer than 51 CD4 cells per cubic millimeter, people of color were admitted 20% more often, had 35% more inpatient days per person-year, and had only 74% as many HIV clinic visits as their White counterparts. CONCLUSIONS: These results indicate that CD4 lymphocyte count is strongly associated with increased usage of health services. People of color with HIV disease are more likely than similar Whites to be admitted to the hospital and less likely to use outpatient care.

Ambulatory Care↗

CD4 counts of normal and HIV-infected south Indian adults: do we need a new staging system?

BACKGROUND: The normal range of CD4 lymphocyte count varies among different ethnic groups. In populations with CD4 counts inherently lower than in the West, the Centers for Disease Control and Prevention (CDC) classification system of HIV-infected individuals may not be appropriate. No such criterion is currently available for ethnic south Indian HIV-infected individuals. We undertook this study to assess the applicability of the western case definition to south Indian HIV patients. METHODS: The CD4 counts of 104 normal and 79 HIV-infected south Indian adults were estimated by flowcytometry. The mean CD4 counts were estimated and compared between CDC groups A, B and C and controls. Receiver operator characteristics curves were generated to determine the cut-off that correlated best with clinical staging for this population. RESULTS: The mean CD4 and CD8 cell counts/microl and the CD4/CD8 ratio of the control group were 799.0, 919.6 and 0.94, respectively. For CDC groups A, B and C, the mean CD4 counts/microl were 454.4, 254.4 and 168; mean CD8 counts/microl were 1156, 1070.9 and 1191.3; and mean CD4/CD8 ratios were 0.44, 0.25 and 0.15, respectively. CONCLUSION: The mean CD4 count among normal south Indians is significantly lower than that in the western population and parallels that of the Chinese. When categorized based on the CDC classification system, the mean CD4 count of HIV-infected individuals was lower. Categories of CD4 counts > 300, 81-300 and < or =80 cells/microl and CD4% > 14, 7-14 and < or = 6 correlate better with disease progression among HIV-infected individuals. A longitudinal study is required before guidelines for the Indian population can be devised.

Adolescent↗

Serum leptin and CD4+ T lymphocytes in HIV+ children during highly active antiretroviral therapy.

OBJECTIVE: Because leptin, the adipocyte-derived hormone, affects thymocyte survival, proliferation of naïve T lymphocytes and the production of proinflammatory cytokines, we aimed to investigate the role of this molecule in immunoreconstitution during highly active antiretroviral therapy (HAART). DESIGN: Prospective longitudinal cohort study. A series of 20 HIV+ children were studied. The subjects were grouped by their increase in serum leptin levels after HAART. METHODS: All participants were weight-stable, free of endocrine disorders and opportunistic infections and equally distributed for sex (males, n=10; females, n=10). Body mass index (BMI), serum lipids, leptin, CD4+ T cells and HIV-1 RNA were measured before initiation of HAART and after a 2-year follow-up. RESULTS: Serum leptin concentration positively correlated with CD4+ lymphocyte number before treatment. HAART significantly reduced viraemia and increased serum levels of lipids in all patients, whereas a significant increase in CD4+ cells and serum leptin was observed in the majority of patients. Notably, in children where HAART was not effective in increasing CD4+ lymphocyte counts, serum leptin did not increase. CONCLUSION: To our knowledge, these findings reveal for the first time a novel link among CD4+ T lymphocytes, serum leptin and highly active anteretroviral theraphy.

Antiretroviral Therapy, Highly Active↗

Correlation of serum antigen and antibody concentration with clinical features in HIV infection.

Serum antigen and antibody values were studied in 164 infants and children infected perinatally with HIV. HIV antigens p17, p24, gp41, and gp120 were determined in sera by immunoblot and antigen capture assays. Lymphocyte blast transformation, serum immunoglobulins, and circulating immune complexes were also evaluated. Altogether 50 patients had HIV antigens measured: 31 (62%) patients had p17 antigen in the serum and 29 (58%) had p24 antigen present. In 19 (38%) and nine (18%) patients, respectively, gp120 and gp41 were detected. All four HIV antigens were detected in seven (14%) patients. There was a positive correlation between the concentration of each HIV sequential specimens were outcome. When sequential specimens were analysed, 120 (73%) patients had p24 antigen present. Patients with stage P2B and P2D (Centers for Disease Control classification) had the highest concentrations of p24 antigen with a mean of approximately 200 pg/ml. Altogether 70% of patients with a p24 antigen concentration of greater than 30 pg/ml eventually died or had severe clinical disease within six to 24 months. Infants under 15 months of age with a p24 antigen concentration as low as 5 pg/ml also did poorly. Increased immunoglobulins and decreases in mitogenic responses and absolute CD4+ lymphocyte counts were more prevalent in patients with raised p24 antigen. Raised concentrations of circulating immune complexes were seen in the symptomatic phase of the disease whereas in the terminal stage of the disease raised serum antigen and a decrease in circulating immune complexes and absolute CD4+ lymphocyte count were evident. Loss of p24 and/or p17 antibody as well as a decreasing ELISA optical density for HIV antibody also signalled progression of the disease.

Antigen-Antibody Complex↗

Response to interferon-alpha in patients with hairy cell leukemia relapsing after treatment with 2-chlorodeoxyadenosine.

2-Chlorodeoxyadenosine (2-CdA) has recently established itself as an extremely effective therapy for patients with hairy cell leukemia. To date, the issue of how to treat patients relapsing after 2-CdA has not been adequately addressed. In our initial study, 41 of 46 patients achieved an objective response (complete or partial remission). The only persistent toxicity associated with this agent appears to be significant suppression of CD4+ lymphocyte counts, albeit without evidence of clinical sequelae at a median follow-up of 30 months (range, 7-43). Eight patients have developed recurrent disease 3-23 months (median, 16 months) after 2-CdA. Because of progressive cytopenias, three of these patients were treated with interferon-alpha (IFN-alpha) (3 x 10(6) units subcutaneously three times per week), commencing 2, 9 and 16 months after the documentation of relapse. All three patients have shown an objective response with reduction of marrow hairy cells and amelioration of neutropenia and thrombocytopenia (two patients, complete remission; one patient, partial remission). Responses were maintained while on IFN-alpha, but two patients relapsed shortly (3 and 4 months, respectively) after discontinuation of IFN. There was no significant toxicity. Prior to commencing IFN-alpha, 22-36 months after 2-CdA, these patients' absolute CD4+ counts were suppressed (mean 211/microliters, s.d. +/- 85/microliters), but have not significantly changed after 10, 11 and 18 months of IFN-alpha therapy (mean 225/microliters, s.d. +/- 93/microliters). These results suggest that in hairy cell leukemia patients relapsing after 2-CdA, IFN-alpha may be a reasonable therapeutic option, especially if persistent CD4+ lymphocytopenia is present.

Adult↗

Impact of inversion of the CD4/CD8 ratio on the natural history of HIV-1 infection.

BACKGROUND: HIV-1 infection is characterized by an inverted CD4/CD8 T-cell ratio, but the distribution of inversions over time after seroconversion and whether delay of inversion is associated with a favorable prognosis are not known. METHODS: T-cell counts and clinical outcomes among men in the Multicenter AIDS Cohort Study who had incident HIV-1 infection before December 31, 1995 were analyzed by Kaplan-Meier and Cox proportional hazards methods. Results were also analyzed by time-dependent multivariate methods to adjust for CD4 lymphocyte counts, viral loads, age, race, and polymorphisms in host chemokine receptor genes (CCR5-Delta32 and CCR2-64I). RESULTS: Among 424 cases whose date of seroconversion was known to within +/-4.5 months, 317, 52, and 55 inverted their CD4/CD8 ratio within less than 1, 1 to 2, and more than 2 years of seroconversion, respectively. Longer time to inversion was significantly associated with longer time to AIDS, even after adjusting for CD4 lymphocyte count and viral load at the first seropositive visit and over the first 3 seropositive visits. Of the 6 seroconverters who had more than 500 CD4 lymphocytes 10 years after seroconversion without receiving highly active antiretroviral therapy, 5 took more than 2 years to invert their CD4/CD8 ratio. CONCLUSIONS: Time from HIV-1 seroconversion to inversion of the CD4/CD8 ratio independently predicted time to AIDS. Early measurements of the CD4/CD8 ratio until inversion occurs may identify people likely to become long-term nonprogressors or slow progressors, thus facilitating detailed studies of the mechanism of HIV-1 disease progression.

Adult↗

[Oral manifestations, CD4+ T-lymphocytes count and viral load in Brazilian and North-American HIV-infected children].

Oral manifestations related to HIV infection were evaluated in 184 children of both genders, aging 0-13 years. The oral exams were carried out at the Ambulatory of Pediatric AIDS, São Lucas Hospital and at the Clinics Hospital, both in Porto Alegre, RS, Brazil, and at the University Hospital and School of Dentistry, State University of New York, Stony Brook, NY, USA, from January 1999 to May 2000. A high prevalence of oral manifestations was observed both in Brazilian (72.73%) and American (53.66%) children. The most frequent manifestations were cervical lymphadenopathy, swelling of the parotids, erythematous candidiasis, petechia, gingivitis, xerostomia and angular cheilitis. Children with oral manifestations had almost normal counts of CD4+ T lymphocytes and high viral load.

Adolescent↗

Persistent coccidioidal seropositivity without clinical evidence of active coccidioidomycosis in patients infected with human immunodeficiency virus.

We retrospectively identified 13 patients infected with human immunodeficiency virus (HIV) who had persistently positive coccidioidal serological tests without evidence of active coccidioidomycosis--to our knowledge, a heretofore undescribed phenomenon. The median duration of follow-up was 19 months. Five patients developed active coccidioidomycosis during this follow-up period; the median interval from the initial positive serological test to the development of active disease was 23 months. There were no significant differences between patients who developed active coccidioidomycosis and those who did not with regard to CD4 lymphocyte count or previous antifungal therapy. Moreover, when all 13 patients were compared with 21 patients who had HIV infection and active coccidioidomycosis, no differences were found with regard to age, race, risk factor for HIV infection, or initial CD4 lymphocyte count. In summary, persistently positive coccidioidal serological tests in HIV-infected patients appear to represent true coccidioidal infection and are associated with a significant risk of the development of active coccidioidomycosis.

Adult↗

Fibroblast-derived factors preserve viability in vitro of mononuclear cells isolated from subjects with HIV-1 infection.

OBJECTIVE: Peripheral blood mononuclear cells (PBMC) from HIV-infected subjects have an increased mortality rate (MR) when incubated in vitro for 3 days in a culture medium. We have previously shown that fibroblast-conditioned medium (FCM) can preserve viability, without significant activation, of human lymphocytes in vitro. We therefore tested the ability of two FCM and other factors to reduce spontaneous MR in HIV-positive PBMC. METHODS: PBMC were cultured for 3 days in control medium and medium supplemented with FCM or recombinant cytokines [interleukin (IL)-2, IL-6, IL-7, granulocyte macrophage colony-stimulating factor]. Cells viable at day 3 were counted in a cytofluorimeter after staining with ethidium bromide. DNA was extracted from the cultures and evaluated for the presence of low molecular weight fragmentation. RESULTS: The MR of PBMC from 51 HIV-positive subjects and from 21 healthy controls were 30.1 and 9.5%, respectively (P < 0.0001). The MR was higher in 40 patients with a CD4+ lymphocyte count < 400 x 10(6)/l than in subjects with a count > 400 x 10(6)/l (32.84 versus 20.96%; P = 0.047). IL-2 and FCM significantly reduced MR in HIV-positive subjects (MR: 17.8 and 20.4%; P: < 0.001 and 0.005, respectively). This effect was more evident in subjects with a CD4+ lymphocyte count < 400 x 10(6)/l and in subjects with negative p24 antigenaemia. Cellular proliferation accounts for increased survival in IL-2-supplemented cultures but not in those with FCM. DNA was extracted from fresh PBMC and cells cultured for 3 days for 22 HIV-positive cases. DNA degradation was documented and bands related to an apoptotic mechanism of death observed, especially in subjects with more advanced disease. CONCLUSIONS: Our data suggest that FCM inhibits accelerated cell death in vitro of PBMC isolated from HIV-positive patients.

Adult↗

Phase I study of 2'-3'-dideoxyinosine administered orally twice daily to patients with AIDS or AIDS-related complex and hematologic intolerance to zidovudine.

PURPOSE: To evaluate the safety and hematologic tolerance of 2'-3'-dideoxyinosine (didanosine, ddI) in subjects with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex and prior hematologic intolerance to zidovudine. PATIENTS AND METHODS: A Phase I trial with two dose groups at a single-center, university-affiliated hospital ambulatory care center. Of 30 subjects enrolled, 21 had AIDS and nine had AIDS-related complex. All had CD4 lymphocyte counts less than 0.2 x 10(9)/L at entry. Didanosine was administered orally twice daily at a total daily dose of 750 mg or 1,500 mg for 12 weeks. Subjects who completed the 12-week study continued to receive ddI at the lower dose. All subjects were monitored for toxicity. Virologic and immunologic response markers were also measured. RESULTS: For the group as a whole, there was no significant decrease in mean hemoglobin level or leukocyte or platelet counts. The dose-limiting toxicity was peripheral neuropathy. Other significant toxicities included pancreatitis and hypocalcemia. Uric acid elevations were common but were without clinical consequence. A sustained decrease in serum p24 antigen of at least 50% was noted in 42% of subjects who were p24 antigen-positive at entry. The mean CD4 lymphocyte count showed an initial increase that was not sustained over the 12-week study. All subjects remained anergic to skin testing. CONCLUSIONS: Didanosine is well tolerated hematologically in some patients with prior significant hematologic intolerance to zidovudine. The toxicity profile for ddI differs from that of zidovudine and includes peripheral neuropathy and pancreatitis. Changes in CD4 lymphocyte number and HIV p24 antigen levels in some patients suggest antiviral activity of ddI in this population.

AIDS-Related Complex↗

Menstrual symptoms in women infected by the human immunodeficiency virus.

OBJECTIVE: To determine whether there is a higher prevalence of menstrual symptoms in women seropositive for the human immunodeficiency virus (HIV) compared to a matched control group and to examine the relation between menstrual symptomatology and immunosuppression. METHODS: In a cross-sectional study, 55 HIV-seropositive women and a matched control group underwent detailed gynecologic assessment. The prevalence of regular cycles, oligomenorrhea, amenorrhea, menorrhagia, dysmenorrhea, and dyspareunia was assessed in the two groups. Any association with clinical disease or CD4 lymphocyte count was sought. RESULTS: There were no significant differences in the prevalence of oligomenorrhea, amenorrhea, menorrhagia, dysmenorrhea, or dyspareunia between the groups. Furthermore, no differences were demonstrated between symptomatic and asymptomatic women infected by HIV, nor was any correlation found between CD4 lymphocyte count and menstrual loss or dysmenorrhea. CONCLUSION: Infection with HIV and related immunosuppression do not seem to have a clinically significant effect on menstruation.

Adult↗