Kaposi's sarcoma-associated herpesvirus-specific immune reconstitution and antiviral effect of combined HAART/chemotherapy in HIV clade C-infected individuals with Kaposi's sarcoma.

BACKGROUND: Kaposi's sarcoma-associated herpesvirus (KSHV) is endemic in South Africa and the clinical manifestation of AIDS-associated Kaposi's sarcoma (KS) represents a significant clinical problem. Whereas the positive effects of HAART on the regression of KS have been well established, less is known about the role of herpesvirus-specific cellular immunity in disease improvement. DESIGN: Thirty-three treatment-naive HIV clade C-infected individuals with KS were randomly assigned into two treatment arms (HAART plus systemic chemotherapy versus HAART alone). KSHV-specific cellular immune responses, viral loads and clinical outcome were evaluated. METHODS: KSHV, Epstein-Barr virus and HIV-specific cellular immunity was measured using an IFN-gamma enzyme-linked immunospot assay in samples obtained at baseline and up to 11 months after treatment initiation. Cell-associated KSHV viremia was determined by real-time polymerase chain reaction. RESULTS: Robust increases in CD4 cell counts and suppressed HIV viral loads were seen in parallel with significant increases in the KSHV-specific cellular immune responses over time. Although slowly increasing after 5 months, KSHV-specific T-cell responses were significantly elevated only after 11 months, with both lytic and latent antigens being more frequently targeted. A trend towards better clinical outcome with HAART plus chemotherapy treatment was observed compared with HAART alone, and was accompanied by a significant reduction in cellular KSHV viral load in the HAART plus chemotherapy-treated subjects but not those treated with HAART alone after 11 months of treatment. CONCLUSION: The data show a temporal association between the clinical improvement of KS and the re-appearance of KSHV-specific cellular immunity, and demonstrate an effective suppression of KSHV viral replication using combination therapy.

Generic antiretroviral efficacy in AIDS-associated Kaposi's sarcoma in sub-Saharan Africa.

Generic antiretroviral drugs are pivotal in the implementation of WHO's '3 by 5' programme. However, clinical experience with generics in sub-Saharan Africa is insufficiently documented. We report on 50 patients with HIV-associated Kaposi's sarcoma treated with generic fixed-dose highly active antiretroviral therapy. At 52 weeks, 74% achieved an undetectable viral load of < 50 copies/ml, 86% achieved < 400 copies/ml, and a 3.1 log10 decline from baseline. Side-effects were minimal. The outcomes support the use of generic antiretroviral therapy.

Functional and genetic analysis of coreceptor usage by dualtropic HIV-1 subtype C isolates.

It is widely documented that a complete switch from the predominant CCR5 (R5) to CXCR4 (X4) phenotype is less common for HIV-1 subtype C (HIV-1C) compared to other major subtypes. We investigated whether dualtropic HIV-1C isolates represented dualtropic, mixed R5 and X4 clones or both. Thirty of 35 functional HIV-1 env clones generated by bulk PCR amplification from peripheral blood mononuclear cells (PBMCs) infected with seven dualtropic HIV-1C isolates utilized CXCR4 exclusively. Five of 35 clones displayed dualtropism. Endpoint dilution of one isolate did not yield a substantial proportion of R5-monotropic env clones. Sequence-based predictive algorithms showed that env sequences from PBMCs, CXCR4 or CCR5-expressing cell lines were indistinguishable and all possessed X4/dualtropic characteristics. We describe HIV-1C CXCR4-tropic env sequence features. Our results suggest a dramatic loss of CCR5 monotropism as dualtropism emerges in HIV-1C which has important implications for the use of coreceptor antagonists in therapeutic strategies for this subtype.

Therapeutic response of HIV-1 subtype C in African patients coinfected with either Mycobacterium tuberculosis or human herpesvirus-8.

BACKGROUND: A potential confounding factor in the treatment of human immunodeficiency virus (HIV) infection in Africa is the frequent occurrence of opportunistic infections (OIs). OI-induced immune activation can interfere with HIV-1 clearance by increasing viral replication and target cell availability. STUDY DESIGN: Treatment outcomes for patients dually infected with HIV-1 and Mycobacterium tuberculosis or HIV-1 and human herpesvirus (HHV)-8 were assessed by measuring changes in viral load and CD4(+) cell counts and by determining the time taken to reach undetectable HIV-1 RNA levels, assessed by means of Kaplan-Meier survival analysis. Patients with HIV-1 and Kaposi sarcoma (KS) received generic nevirapine, stavudine, and lamivudine (3TC); patients with HIV-1 and tuberculosis (TB) received standard commercial didanosine, 3TC, and efavirenz. RESULTS: Both cohorts exhibited a rapid, near-exponential phase I decline in viral load. Patients with TB and late-stage KS had the steepest decay kinetics. These same patients had the greatest initial increase in CD4(+) cell counts. Phase II clearance was slower and more variable. The proportions of patients reaching undetectable plasma HIV-1 levels at days 7, 14, 28, 60, and 90 were, respectively, 15.8%, 30.0%, 52.6%, 78.9%, and 93.8% (Pearson's chi 2=50.5; P<.001) for patients with TB and 0.0%, 5.0%, 22.2%, 64.7%, and 80.0% (Pearson's chi 2=63.6; P<.001) for patients with KS. CONCLUSIONS: Nucleoside reverse-transcriptase inhibitor/nonnucleoside reverse-transcriptase inhibitor-based treatment regimens are highly effective in clearing rapidly replicating (phase I) virus in African patients dually infected with HIV-1 and either TB or KS.

Mother-to-child transmission of human herpesvirus-8 in South Africa.

To investigate transmission of human herpesvirus (HHV)-8, 2546 mother-child pairs were recruited from rural clinics in South Africa and were tested for antibodies against lytic and latent HHV-8 antigens. The prevalence of antibodies in children increased with increasing maternal antibody titer (lytic, chi 21=26, and P<.001; latent, chi 21=55, and P<.001). HHV-8 DNA was detectable in 145 of 978 maternal saliva samples (mean virus load, 488,450 copies/mL; range, 1550-660,000 copies/mL) and in 12 of 43 breast-milk samples (mean virus load, 5800 copies/mL; range, 1550-12,540 copies/mL). The prevalence of HHV-8 DNA in maternal saliva was unrelated to latent anti-HHV-8 antibody status but was higher in mothers with the highest titers of lytic antibodies than in other mothers (34% vs. 8%; P<.001). The prevalence of lytic anti-HHV-8 antibodies in children was 13% (70/528) if the mother did not have HHV-8 in saliva and was 29% (8/28) if the mother had a high HHV-8 load (>50,000 copies/mL) in saliva (odds ratio, 2.6; 95% confidence interval, 1.1-6.2). The presence of HHV-8 DNA in maternal saliva was unrelated to latent antibodies in children. Saliva could be a route of transmission of HHV-8 from person to person, although other routes cannot be ruled out.