Evaluation of plasma human herpesvirus 8 DNA as a marker of clinical outcomes during antiretroviral therapy for AIDS-related Kaposi sarcoma in Zimbabwe.

BACKGROUND: The usefulness of plasma human herpesvirus 8 (HHV-8) DNA as a marker of response to treatment for acquired immunodeficiency syndrome-associated Kaposi sarcoma (AIDS-KS) in an African setting is unknown. METHODS: We conducted a prospective pilot study at the Parirenyatwa Hospital Kaposi Sarcoma Clinic (Harare, Zimbabwe) to investigate the hypothesis that the clinical response of AIDS-KS is associated with suppression of HHV-8 DNA. Antiretroviral therapy (ART) was provided as coformulation of abacavir, lamivudine, and zidovudine. Clinical response was defined as survival to week 96 with either complete or partial resolution of KS disease. RESULTS: Ninety ART-naive participants (62 men and 28 women) aged >18 years who had human immunodeficiency virus type 1 (HIV-1) infection and biopsy-confirmed KS were studied; 82% had stage T1 disease. Fifty participants received adjunctive chemotherapy. The median CD4(+) lymphocyte count increased from 124 cells/microL at baseline to 281 cells/microL, the plasma HIV-1 RNA level decreased from 4.69 to <2.60 log(10) copies/mL, the plasma HHV-8 DNA level decreased from 660 to <25 copies/mL, and HHV-8 DNA level in peripheral blood mononuclear cells decreased from 2790 to 37 copies/10(6) cells (P < .001 for each comparison). There were 14 deaths (16%) and 13 patients (15%) lost to follow-up. The most common cause of death was infection. Clinical response of KS occurred in 17 participants (19%). Pretreatment plasma HHV-8 DNA levels of <660 copies/mL were associated with greater survival (odds ratio, 2.83; 95% confidence interval, 1.07-7.53; P = .04) and a better clinical response (odds ratio, 6.38; 95% confidence interval, 1.68-24.19; P = .006). CONCLUSIONS: AIDS-KS tumor responses after ART initiation were limited. Pretreatment plasma HHV-8 DNA level may be a surrogate for KS disease that is in need of intensive clinical management.

Lack of evidence for frequent heterosexual transmission of human herpesvirus 8 in Zimbabwe.

BACKGROUND: There is conflicting evidence about the contribution of heterosexual transmission to the spread of human herpesvirus 8 (HHV-8) in southern Africa. This study evaluated the hypothesis that HHV-8 infection is associated with risk factors for human immunodeficiency virus type 1 (HIV-1) and other sexually transmitted infections among Zimbabwean men. METHODS: HHV-8 seroprevalence was determined for 2750 participants in the Zimbabwe AIDS Prevention Project cohort of male factory workers in Harare, Zimbabwe. Potential associations of HHV-8 antibody detection with risk factors for HIV-1 infection were examined by univariate analysis. Variables with P < .1 in the univariate analysis were included in a multivariate logistic regression model. HHV-8 seroprevalence was also determined among 297 heterosexual couples. RESULTS: Prevalence of HHV-8, HIV-1, and HHV-8 and HIV-1 coinfection was 28.5% (95% confidence interval [CI], 26.8%-30.2%), 19.5% (95% CI, 18.0%-20.9%), and 6.5% (95% CI, 5.6%-7.5%), respectively. Detection of HHV-8 antibodies was independently associated with older age and HIV-1 infection but not with number of recent sex partners, marital status, education, condom use, prior sexually transmitted infections, payment for sex, chronic hepatitis B infection, or incident HIV-1 infection. HHV-8 seroprevalence was 31.7% (95% CI, 26.3-37.0) among wives in the couples tested, but HHV-8 infection of wives was not associated with HHV-8 infection of husbands (odds ratio, 1.08; 95% CI, 0.62-1.88; P = .8). CONCLUSIONS: HHV-8 and HIV-1 infection did not have common sexual risk factors among urban Zimbabwean men. Sexual transmission does not explain the high prevalence of HHV-8 in this population.

Genetic diversity of the Kaposi's sarcoma herpesvirus K1 protein in AIDS-KS in Zimbabwe.

BACKGROUND: Kaposi's sarcoma-associated herpesvirus (KSHV) encodes genetically diverse K1 alleles which have unique geographic distributions. Little is known about K1 genetic diversity in Zimbabwe where acquired immunodeficiency syndrome-associated KS (AIDS-KS) is epidemic. OBJECTIVE: Evaluate K1 diversity in Zimbabwe and compare Zimbabwean K1 diversity to other areas in Africa. STUDY DESIGN: K1 nucleotide sequence was determined for AIDS-KS cases in Zimbabwe. K1 references sequences were obtained from Genbank. RESULTS: Among 65 Zimbabwean AIDS-KS cases, 26 (40%) were K1 subtype A and 39 (60%) were subtype B. Zimbabwean subtype A sequences grouped only with African intratype A5 variants. Zimbabwean subtype B sequences grouped with multiple intratype African variants: 26 B1 (26%), four B3 (6%) and nine highly divergent B4 (14%). Zimbabwean subtype B had a lower synonymous to nonsynonymous mutation ratio (median 0.59 versus 0.66; P=0.008) and greater distance to the most recent common ancestor (median 0.03 versus 0.009; P<0.001) compared to subtype A. Within the B subgroup, the distribution of intratype B variants differed in Zimbabwe and Uganda (P=0.004). CONCLUSIONS: Greater positive selection and genetic diversity in K1 subtype B compared to subtype A5 exist in Zimbabwe. However, there were no significant associations between K1 subtype and the clinical or demographic characteristics of AIDS-KS cases.

Immune reconstitution inflammatory syndrome associated with Kaposi sarcoma during potent antiretroviral therapy.

Rapidly progressive Kaposi sarcoma (KS) lesions with lymphadenopathy and tissue swelling occurred in a patient during antiretroviral treatment, despite an increased CD4(+) lymphocyte count and decreased HIV-1 level and KS-associated herpesvirus replication, suggesting immune reconstitution inflammatory syndrome. Inflammation resolved coincident with decreases in the CD4(+) lymphocyte count during paclitaxel treatment, whereas KS cleared only after prolonged antiretroviral therapy and chemotherapy.

Relationship of Kaposi sarcoma (KS)-associated herpesvirus viremia and KS disease in Zimbabwe.

The relationship between Kaposi sarcoma-associated herpesvirus (KSHV) viremia and KS disease was investigated in 500 subjects who received treatment in Harare, Zimbabwe. Subjects were grouped by results of human immunodeficiency virus (HIV) type 1 serological tests, KS diagnosis, and KS clinical stage. The plasma KSHV DNA concentration was associated with concomitant KS and HIV-1 infection (AIDS-KS; P<.001) and AIDS-KS clinical stage (P=.01). Plasma KSHV DNA levels were greater in AIDS-KS than in matched HIV-1-seronegative KS (P=.04). The plasma KSHV DNA level was not associated with age, sex, systemic symptoms, or CD4+ lymphocyte count. Plasma and peripheral blood mononuclear cell KSHV DNA concentrations were linearly related (r2=.44; P<.001), and the nucleotide sequence of the K1 gene highly variable region was identical in both compartments. These findings provide evidence that KSHV viremia is common in advanced AIDS-KS in Zimbabwe and suggest a relationship between KSHV lytic replication and untreated HIV-1 infection.

Predictors of immune reconstitution inflammatory syndrome-associated with kaposi sarcoma in mozambique: a prospective study.

BACKGROUND: The impact and relevance of immune reconstitution inflammatory syndrome-associated with Kaposi sarcoma (IRIS-KS) has not been assessed in sub-Saharan African countries, where the bulk of HIV-1 and KS-associated herpesvirus (KSHV) coinfection occurs. Understanding the risk factors for developing IRIS-KS would aid in the identification and in the improvement of clinical management for high-risk patients. METHODS: Sixty-nine consecutive HIV-1 and KSHV coinfected Mozambican adults initiating cART were prospectively followed for development of IRIS-KS over 10 months as part of a larger prospective observational study. Plasma HIV RNA, CD4 counts, anti-KSHV lytic antibodies, and plasma KSHV DNA viral load were assessed at the pre-cART visit and at 4 and 10 months after cART initiation. A survival analysis was performed to assess potential risk factors for developing IRIS-KS. RESULTS: During the first 10 months of combined antiretroviral therapy (cART), 8 patients (8/69, 11.6%) experienced IRIS-KS at a median time of 13.8 weeks after cART initiation. Multivariate analysis identified 4 independent IRIS-KS predictors: clinical pretreatment KS [hazard ratio (HR) 91.7], detectable plasma KSHV DNA (HR 24.4), hematocrit <30% (HR 26.5), and plasma HIV-1 RNA viral load (HR 34.6 per log viral load increase). Treatment with either cART alone or with a combination of cART and systemic chemotherapy led to partial or complete clinical response in 62.5% (5/8) of IRIS-KS cases. CONCLUSIONS: This study identified 4 independent predictors of IRIS-KS, which may help to develop screening tools aiding in the identification of patients at high risk of IRIS-KS for whom close clinical supervision is warranted.

Persistence of Kaposi sarcoma-associated herpesvirus (KSHV)-infected cells in KSHV/HIV-1-coinfected subjects without KSHV-associated diseases.

Inguinal lymph nodes from 24 human immunodeficiency virus (HIV) type 1-infected subjects without Kaposi sarcoma-associated herpesvirus (KSHV)-associated diseases were examined for KSHV infection. KSHV-infected cells were detected at a very low frequency in the lymph nodes of 7 subjects (median frequency, 2 infected cells/10(7) lymph node cells). Latent, but not lytic, KSHV gene expression was detected and KSHV-infected cells were located in B cell-rich areas of lymph node follicles. These findings provide evidence that, in the absence of KSHV-associated diseases, latent infection of lymph node cells provides a mechanism for the persistence of KSHV in KSHV/HIV-1-coinfected persons.