Mapping research evidence on quality of life in children with atopic dermatitis in sub-Saharan Africa: a scoping review protocol.

BACKGROUND: Atopic dermatitis (AD) is a chronic, debilitating disease affecting children worldwide. Several studies have shown the disease to be a significant problem which leads to a diminished quality of life (QoL) for the affected children, but systematic evaluation of such studies in Africa is yet to be reported. Therefore, this scoping review aims to map research evidence on children with AD and their QoL in sub-Saharan Africa (SSA). METHODS: The scoping review will follow the Arksey and O'Mally methodological framework. The electronic databases to be searched will include PubMed, EBSCOhost (Academic Search Complete, CINAHL, PsycINFO, and Health Sources), and Scopus and Google Scholar, for published literature between 2010 and 2021. The search strategy for the databases will include keywords, Medical Subject Headings terms, and Boolean operators. The reference list of the included sources of evidence and the WHO website will also be consulted for evidence relating to QoL of children with AD in SSA. Two independent reviewers will undertake abstract and full-text article screening with the guidance of eligibility criteria. This review will include studies conducted in SSA, and publications focusing on QoL and associated factors of AD in children. Data will be extracted from the included studies and analyzed qualitatively; NVIVO software V.11 will be used, and the emerging themes reported narratively. The mixed-method appraisal tool (MMAT) will be employed for quality appraisal of included studies. DISCUSSION: We look forward to the findings of several studies that describe the QoL and associated factors among children with AD and that report on the use of different diagnostic criteria, severity scaling and QoL measuring scale tools used to ascertain the presence of AD, scale the severity of AD, and the impact of AD on QoL among children. This will help to improve clinical practice and the QoL of children with AD in SSA. The study findings will be disseminated through publication in a peer-reviewed journal, peer presentations, and presentations at relevant conferences. CONCLUSION: This study will add new knowledge on the QoL in children with AD in the SSA context. The study has the potential to inform research and clinical practice to impact the QoL of children with AD in SSA.

Epidermal barrier function in human immunodeficiency virus-infected South African infants compared with uninfected.

BACKGROUND AND OBJECTIVE: Infant human immunodeficiency virus (HIV) infection remains a problem in different parts of the world. Early signs of disease manifestation often involve infant skin. This study compared the skin barrier properties of HIV infected with uninfected infants. METHODS: A cross-sectional descriptive study was undertaken with HIV positive and HIV negative unexposed African infants (6 weeks-12 months). Both had normal birth weight for age, no pre-existing dermatoses or co-infections, and received all their vaccinations timeously. The HIV positive infants were on antiretroviral (ARV) therapy. The skin barrier quality was assessed by measuring the transepidermal water loss (TEWL) and skin surface hydration (SSH) on the dorsal arm (1) and the inner forearm (2). RESULTS: Eighty-six HIV negative and 43 HIV positive African children were recruited. There were significant differences between the two groups based on the presence of HIV infection. In both sites, measured TEWL rates were significantly higher for the HIV positive children. There was a nonsignificant difference between the SSH values for site 1 and a marginally significant difference for site 2, with the average values higher in the HIV positive group. In both groups, TEWL rates and SSH values were significantly lower on site 1 compared to site 2. CONCLUSION: Differences in skin barrier properties of HIV infected and uninfected children may exist. The altered skin barrier in infected children may be one of the factors that predisposes them to various inflammatory and infectious dermatoses. Improving the skin barrier may assist in preventing these conditions.

An Update on Adverse Cutaneous Drug Reactions in HIV/AIDS.

BACKGROUND: The global mortality from HIV and the cutaneous burden of infective, inflammatory and malignant diseases in the setting of AIDS have significantly declined following the advent of highly active antiretroviral therapy. Regrettably, there has been a contemporaneous escalation in the incidence of adverse cutaneous drug reactions (ACDR), with studies attesting that HIV-positive individuals are a hundred times more susceptible to drug reactions than the general population, and advanced immunodeficiency portending an even greater risk. Several variables are accountable for this amplified risk in HIV. SUMMARY: Adverse reactions to trimethoprim-sulfamethoxazole are the most common, increasing from approximately 2-8% in the general population over to 43% amongst HIV-positive individuals to approximately 69% in subjects with AIDS. Antituberculosis drugs and antiretrovirals are also well-known instigators of ACDR. Cutaneous reactions range from mild morbilliform eruptions to severe, life-threatening manifestations in the form of Stevens-Johnson syndrome/toxic epidermal necrolysis. Histological features vary from vacuolar interface changes to full-thickness epidermal necrosis with subepidermal blister formation. A precipitous diagnosis of the ACDR, clinically and histologically if necessary, together with the isolation of the causative drug is critical. The identification process, however, is often complex and multifaceted due to polypharmacy and inconclusive data on which drugs are the most likely offending agents, especially against the background of tuberculosis co-infection. KEY MESSAGES: Whilst milder cutaneous reactions are treated symptomatically, severe reactions mandate immediate treatment discontinuation without rechallenge. Further studies are required to establish safe rechallenge guidelines in resource-limited settings with a high HIV and tuberculosis prevalence.

Primary Cutaneous Anaplastic Large-Cell Lymphoma.

A 35-year-old male presented with a 6-month history of asymptomatic, generalised, self-healing lesions. On clinical examination, there were diffuse, ulcerated, necrotic papules and nodules with lymphoedema of the face. Histology sections confirmed atypical lymphoid-type cells which appeared round-to-oval with irregular nuclei (horseshoe-shaped). Immunohistochemistry stains were positive for CD30, CD3, and epithelial membrane antigen. The features were in keeping with an anaplastic large-cell lymphoma, T cell type. This transformed into a systemic variant of the disease after the patient had completed chemotherapy.

The Diagnosis of Fungal Neglected Tropical Diseases (Fungal NTDs) and the Role of Investigation and Laboratory Tests: An Expert Consensus Report.

The diagnosis of fungal Neglected Tropical Diseases (NTD) is primarily based on initial visual recognition of a suspected case followed by confirmatory laboratory testing, which is often limited to specialized facilities. Although molecular and serodiagnostic tools have advanced, a substantial gap remains between the desirable and the practical in endemic settings. To explore this issue further, we conducted a survey of subject matter experts on the optimal diagnostic methods sufficient to initiate treatment in well-equipped versus basic healthcare settings, as well as optimal sampling methods, for three fungal NTDs: mycetoma, chromoblastomycosis, and sporotrichosis. A survey of 23 centres found consensus on the key role of semi-invasive sampling methods such as biopsy diagnosis as compared with swabs or impression smears, and on the importance of histopathology, direct microscopy, and culture for mycetoma and chromoblastomycosis confirmation in well-equipped laboratories. In basic healthcare settings, direct microscopy combined with clinical signs were reported to be the most useful diagnostic indicators to prompt referral for treatment. The survey identified that the diagnosis of sporotrichosis is the most problematic with poor sensitivity across the most widely available laboratory tests except fungal culture, highlighting the need to improve mycological diagnostic capacity and to develop innovative diagnostic solutions. Fungal microscopy and culture are now recognized as WHO essential diagnostic tests and better training in their application will help improve the situation. For mycetoma and sporotrichosis, in particular, advances in identifying specific marker antigens or genomic sequences may pave the way for new laboratory-based or point-of-care tests, although this is a formidable task given the large number of different organisms that can cause fungal NTDs.

Health-Related Quality of Life in Patients Treated With Antiretroviral Therapy Only Versus Chemotherapy and Antiretroviral Therapy for HIV-Associated Kaposi Sarcoma: A Randomized Control Trial.

PURPOSE: In sub-Saharan Africa, Kaposi sarcoma (KS) is the most common HIV-associated cancer. KS causes substantial morbidity, and treatment goals should emphasize quality of life (QOL). Antiretroviral therapy (ART) is indicated, and early chemotherapy significantly improves tumor regression. The effect of ART alone or with chemotherapy on QOL in treatment-naïve South Africans with HIV-associated KS was assessed. METHODS: KAART (Kaposi Sarcoma AIDS Anti-Retroviral Therapy) is a randomized, controlled, open-label trial of ART versus ART plus chemotherapy. Crossover between arms was allowed for patients with progressive disease. Eighty-nine percent of patients had advanced tumor burden. Within KAART, QOL measured by European Organization for Research and Treatment of Cancer-QLQ-C30 questionnaire evaluated functional and symptom domains and global QOL. Intragroup changes between baseline and month 12 (Wilcoxon rank sign test), changes between the arms (Mann-Whitney test), and the relationship between responses, determined by AIDS Clinical Trial Group criteria and QOL measures (Kruskal-Wallis test), were evaluated. P values < .01 were considered significant. RESULTS: QOL information was available for 111 of 112 patients. Significant improvements over 12 months were seen in global health status and functional scales (emotional, cognitive, and social scales; not physical and role function). Most symptom scales (fatigue, pain, dyspnea, insomnia, appetite, diarrhea, and constipation) also showed significant improvement. There were no statistically significant changes between arms in intention-to-treat analysis. Patients showing a response to the tumor (complete or partial) reported significantly increased global QOL ( P < .001), pain relief, and improved role functioning. Adherence, adverse events, HIV viral load, and CD4 count did not correlate with global QOL. CONCLUSION: African patients with HIV-associated KS derive a significant benefit in QOL from ART and tumor regression.

HAART in hand: The change in Kaposi's sarcoma presentation in KwaZulu-Natal, South Africa.

BACKGROUND: HIV/AIDS-related Kaposi's sarcoma (HIV-KS) is a public health problem in South Africa (SA). It is AIDS defining. There have been no studies evaluating its prevalence since the national roll-out of highly active antiretroviral therapy (HAART). OBJECTIVE: To evaluate the effect of HAART on the disease profile of HIV-KS in KwaZulu-Natal Province (KZN), SA. METHODS: Charts of patients with histologically confirmed HIV-KS were reviewed at an oncology clinic in KZN. The significance of associations of HAART with age, gender, CD4 count, urban/rural residence, fungating lesions, ulceration and lymphoedema, and treatment delay, was determined by t-tests for normally distributed continuous variables and χ2 tests for categorical variables. Logistic regression models were used to analyse the association of HAART with CD4 count. RESULTS: Of 198 patients, 194 were documented as HIV-positive; 168 (86.6%) were on HAART at the time of their KS diagnosis. The mean CD4 count of 266 cells/µL was higher than that in previous studies at this site. The mean age at presentation was 36.6 (standard deviation 10.1) years. Females presented at a younger mean age than males (p<0.001). The mean age of females on HAART was 34.7 years and that of males 39.0 years (p=0.003). HAART-naive patients were three times more likely than those receiving HAART (15.4% v. 4.8%) to have visceral involvement (p=0.03). CONCLUSIONS: HAART use has resulted in outcome improvement. Mean age at presentation has increased in the group as a whole and for females in particular. The trend in mean CD4 counts has shown positive growth. Females no longer shoulder a disproportionate burden of disease.

HIV infection predisposes skin to toxic epidermal necrolysis via depletion of skin-directed CD4⁺ T cells.

BACKGROUND: A greater incidence of adverse cutaneous drug eruptions, including toxic epidermal necrolysis (TEN), occurs among HIV-infected patients. OBJECTIVE: We sought to determine if immunophenotypical differences exist in the inflammatory infiltrates of TEN lesions from HIV-infected individuals versus noninfected individuals. METHODS: The inflammatory infiltrates in 12 cases of TEN from HIV-positive patients were characterized and compared with the infiltrates present in 12 cases of TEN from HIV-negative patients. RESULTS: TEN infiltrates consisted of CD3, CD4, and CD8 immunoreactive T lymphocytes in both the dermis and epidermis. HIV infection was associated with an 8-fold increase in the ratio of CD8(+) to CD4(+) T cells infiltrating the dermis (P = .006) and a decrease in the number of dermal CD4(+) cells (P = .044). There was also a significant decrease in the ratio of CD25(+) to CD4(+) cells in the epidermis of HIV-infected skin (P = .011). LIMITATIONS: This study is limited by small sample sizes. CONCLUSION: A decrease in the number of skin-directed CD4(+) cells and an increase in the ratio of CD8(+) to CD4(+) cells exists in TEN lesions among HIV-infected individuals and likely contribute to an increased risk of developing drug reactions because of the loss of skin-protective CD4(+)CD25(+) regulatory T cells.

Immune reconstitution inflammatory syndrome associated with Kaposi sarcoma: higher incidence and mortality in Africa than in the UK.

OBJECTIVES: To assess the incidence, predictors, and outcomes of Kaposi sarcoma-associated paradoxical immune reconstitution inflammatory syndrome (KS-IRIS) in antiretroviral therapy (ART)-naive HIV-infected patients with Kaposi sarcoma initiating ART in both well resourced and limited-resourced settings. DESIGN: Pooled analysis of three prospective cohorts of ART-naive HIV-infected patients with Kaposi sarcoma from sub-Saharan Africa (SSA) and one from the UK. METHODS: KS-IRIS case definition was standardized across sites. Cox regression and Kaplan-Meier survival analysis were used to identify the incidence and predictors of KS-IRIS and Kaposi sarcoma-associated mortality. RESULTS: Fifty-eight of 417 (13.9%) eligible individuals experienced KS-IRIS with an incidence 2.5 times higher in the African vs. European cohorts (P=0.001). ART alone as initial Kaposi sarcoma treatment (hazard ratio 2.97, 95% confidence interval (CI) 1.02-8.69); T1 Kaposi sarcoma stage (hazard ratio 2.96, 95% CI 1.26-6.94); and plasma HIV-1 RNA more than 5 log10 copies/ml (hazard ratio 2.14, 95% CI 1.25-3.67) independently predicted KS-IRIS at baseline. Detectable plasma Kaposi sarcoma-associated herpes virus (KSHV) DNA additionally predicted KS-IRIS among the 259 patients with KSHV DNA assessed (hazard ratio 2.98, 95% CI 1.23-7.19). Nineteen KS-IRIS patients died, all in SSA. Kaposi sarcoma mortality was 3.3-fold higher in Africa, and was predicted by KS-IRIS (hazard ratio 19.24, CI 7.62-48.58), lack of chemotherapy (hazard ratio 2.35, 95% CI 1.09-5.05), pre-ART CD4 cell count less than 200 cells/µl (hazard ratio 2.04, 95% CI 0.99-4.2), and detectable baseline KSHV DNA (hazard ratio 2.12, 95% CI 0.94-4.77). CONCLUSION: KS-IRIS incidence and mortality are higher in SSA than in the UK. This is largely explained by the more advanced Kaposi sarcoma disease and lower chemotherapy availability. KS-IRIS is a major contributor to Kaposi sarcoma-associated mortality in Africa. Our results support the need to increase awareness on KS-IRIS, encourage earlier presentation, referral and diagnosis of Kaposi sarcoma, and advocate on access to systemic chemotherapy in Africa.

A randomized controlled trial of highly active antiretroviral therapy versus highly active antiretroviral therapy and chemotherapy in therapy-naive patients with HIV-associated Kaposi sarcoma in South Africa.

BACKGROUND: The optimal approach to HIV-associated Kaposi sarcoma (HIV-KS) in sub-Saharan Africa is unknown. With large-scale rollout of highly active antiretroviral therapy (HAART) in South Africa, we hypothesized that survival in HIV-KS would improve and administration of chemotherapy in addition to HAART would be feasible and improve KS-specific outcomes. METHODS: We conducted a randomized, controlled, open-label trial with intention-to-treat analysis. Treatment-naive patients from King Edward VIII Hospital, Durban, South Africa, a public-sector tertiary referral center, with HIV-KS, but no symptomatic visceral disease or fungating lesions requiring urgent chemotherapy, were randomized to HAART alone or HAART and chemotherapy (CXT). HAART arm received stavudine, lamivudine, and nevirapine (Triomune; CXT arm received Triomune plus bleomycin, doxorubicin, and vincristine every 3 weeks. When bleomycin, doxorubicin, and vincristine were not available, oral etoposide (50-100 mg for 1-21 days of a 28-day cycle) was substituted. Primary outcome was overall KS response using AIDS Clinical Trial Group criteria 12 months after HAART initiation. Secondary comparisons included time to response, progression-free survival, overall survival, adverse events, HIV control, CD4 reconstitution, adherence, and quality of life. RESULTS: Fifty-nine subjects were randomized to HAART and 53 to CXT; 12-month overall KS response was 39% in the HAART arm and 66% in the CXT arm (difference, 27%; 95% confidence interval, 9%-43%; P = 0.005). At 12 months, 77% were alive (no survival difference between arms; P = 0.49), 82% had HIV viral load <50 copies per milliliter without difference between the arms (P = 0.47); CD4 counts and quality-of-life measures improved in all patients. CONCLUSIONS: HAART with chemotherapy produced higher overall KS response over 12 months, whereas HAART alone provided similar improvement in survival and select measures of morbidity. In Africa, with high prevalence of HIV and human herpes virus-8 and limited resources, HAART alone provides important benefit in patients with HIV-KS.

Common skin conditions in children with HIV/AIDS.

The most recent Joint United Nations Programme on HIV/AIDS (UNAIDS) data inform us that approximately 2.3 million children were infected with HIV at the end of 2009. The greatest burden of this infection is thrust squarely on the most impoverished healthcare systems in the world. Sub-Saharan Africa is home to at least 68% of the global total of HIV infection of 22.5 million. Although a scale up of antiretrovirals has been one of the UNAIDS priorities, and access to services to prevent mother-to-child transmission has increased, an estimated 370,000 children were newly infected in 2009. Hence, infected mothers continue giving birth to HIV-infected children who require appropriate healthcare to diagnose and treat their underlying immunodeficiency and related disorders. Skin lesions are common in these children as they present with infections common in the general population, albeit more severe. Those lesions that are markers of HIV or AIDS are important signs heralding an improving or declining immune system and the success of antiretrovirals. Cutaneous manifestations of HIV/AIDS can be classified broadly as infections and infestations, inflammatory conditions, tumors, and antiretroviral related. This manuscript discusses the more common skin conditions seen in children infected with HIV so as to improve the diagnosis and therapy administered by healthcare professionals especially in sub-Saharan Africa.

Substantial regional differences in human herpesvirus 8 seroprevalence in sub-Saharan Africa: insights on the origin of the "Kaposi's sarcoma belt".

Equatorial Africa has among the highest incidences of Kaposi's sarcoma (KS) in the world, thus earning the name "KS Belt." This was the case even before the HIV epidemic. To date, there is no clear evidence that HHV-8 seroprevalence is higher in this region but interpretation of the available literature is tempered by differences in serologic assays used across studies. We examined representatively sampled ambulatory adults in Uganda, which is in the "KS Belt," and in Zimbabwe and South Africa which are outside the Belt, for HHV-8 antibodies. All serologic assays were uniformly performed in the same reference laboratory by the same personnel. In the base-case serologic algorithm, seropositivity was defined by reactivity in an immunofluorescence assay or in 2 enzyme immunoassays. A total of 2,375 participants were examined. In Uganda, HHV-8 seroprevalence was high early in adulthood (35.5% by age 21) without significant change thereafter. In contrast, HHV-8 seroprevalence early in adulthood was lower in Zimbabwe and South Africa (13.7 and 10.8%, respectively) but increased with age. After age adjustment, Ugandans had 3.24-fold greater odds of being HHV-8 infected than South Africans (p < 0.001) and 2.22-fold greater odds than Zimbabweans (p < 0.001). Inferences were unchanged using all other serologic algorithms evaluated. In conclusion, HHV-8 infection is substantially more common in Uganda than in Zimbabwe and South Africa. These findings help to explain the high KS incidence in the "KS Belt" and underscore the importance of a uniform approach to HHV-8 antibody testing.

Defining immune reconstitution inflammatory syndrome: evaluation of expert opinion versus 2 case definitions in a South African cohort.

BACKGROUND: There is no validated case definition for human immunodeficiency virus-associated immune reconstitution inflammatory syndrome (IRIS). We measured the level of agreement of 2 published case definitions (hereafter referred to as CD1 and CD2) with expert opinion in a prospective cohort of patients who were starting antiretroviral therapy in South Africa. METHODS: A total of 498 adult patients were monitored for the first 6 months of antiretroviral therapy. All new or worsening clinical events were reviewed by 2 investigators and classified on the basis of expert opinion, CD1, and CD2. Events were categorized according to whether they were paradoxical or unmasking in presentation. We measured positive, negative, and chance-corrected agreement (kappa) with expert opinion for CD1 and CD2, and reviewed areas of disagreement. RESULTS: A total of 620 clinical events were recorded, of which, on the basis of expert opinion, 144 (23.2%) were defined as probable IRIS and 112 (18.1%) were defined as possible IRIS. Of the 144 probable IRIS events, 93 (64.6%) were unmasking in presentation, 99 (68.8%) were associated with dermatological or orogenital disease, and 45 (31.3%) were associated with tuberculosis or major opportunistic infections. Of the 620 clinical events recorded, 41 (6.6%) were classified as IRIS on the basis of CD1, and 156 (25.2%) were classified as IRIS on the basis of CD2. Positive agreement between CD1 and expert opinion was low for both unmasking (17.2%; kappa = 0.24) and paradoxical events (37.3%; kappa = 0.43), mainly because 1 major criterion requires IRIS to be atypical and either an opportunistic infection or a tumor, although negative agreement was >98%. In contrast, CD2 had good positive agreement (>75% for most event types), with a kappa value of 0.75 for paradoxical and 0.62 for unmasking. CONCLUSIONS: CD2 agreed well with expert opinion, with additional clinical events, such as arthropathy and inflammatory dermatoses, being classified as IRIS and added to CD2. We propose revised case definitions for both paradoxical and unmasking IRIS.

Kaposi sarcoma-associated herpesvirus (KSHV) seroprevalence in population-based samples of African children: evidence for at least 2 patterns of KSHV transmission.

BACKGROUND: Kaposi sarcoma-associated herpesvirus (KSHV) infection is endemic among adult populations in Africa. A prevailing view is that childhood transmission is primarily responsible for the high seroprevalence of KSHV among adults that is observed throughout the continent. However, few studies have directly examined children, particularly in locations where KS is not commonly endemic. METHODS: Participants were children aged 1.5-8.9 years, including 427 children from a population-based sample in South Africa, 422 from a population-based sample in Uganda, and 567 from a clinic-based sample in Uganda. All serum specimens were tested by the same laboratory for KSHV antibodies with use of 2 enzyme immunoassays (against K8.1 and ORF65) and 1 immunofluorescence assay. RESULTS: KSHV seroprevalence was 7.5%-9.0% among South African children and was not associated with age. In contrast, in the Ugandan population-based sample, KSHV seroprevalence increased from 10% among 2-year-old children to 30.6% among 8-year-old children (P(trend) < .001). In the Ugandan clinic-based sample, seroprevalence increased from 9.3% among 2-year-old children to 36.4% among 8-year-old children (P(trend) < .001). CONCLUSION: Two distinct relationships between age and KSHV infection among children imply that KSHV transmission among children is not uniform throughout Africa and is therefore not always responsible for the high seroprevalence observed in adults. There are at least 2 patterns of KSHV transmission in Africa.

99mTc-MIBI imaging of AIDS-related Kaposi's sarcoma in the lungs.

OBJECTIVE: Pulmonary Kaposi's sarcoma (KS) occurs in more than 10% of patients with acquired immunodeficiency syndrome (AIDS) and has a high mortality rate. Prompt detection, diagnosis, and treatment reduce patient morbidity and mortality. The objective of this study was to determine the efficacy of 99mTc-hexakis-2-methoxy isobutyl isonitrile (99mTc-MIBI) imaging in detecting pulmonary AIDS-related KS. METHODS: 99mTc-MIBI imaging was performed on 72 human immunodeficiency virus-seropositive patients with bronchoscopic diagnosis of pulmonary KS (36 patients), pneumonia (22), normal tracheo-bronchial tree (11), lymphoma (2), and bronchogenic carcinoma (1). Lung uptake and lymph node detection in KS were compared on planar and single photon emission computed tomography (SPECT) scans. RESULTS: The lung/myocardium ratios on the 1-h planar images were significantly higher in KS and normal lungs than opportunistic infection. Using the lung/myocardium ratio of 1 as cutoff, the sensitivity, specificity, and accuracy of the 1-h planar images for detecting pulmonary KS were 75, 57.58, and 66.67%, respectively. Abnormal lymph node uptake, pleural/pericardial effusions, and ascites were detected more readily on SPECT. CONCLUSION: Planar 99mTc-MIBI imaging has moderate sensitivity, specificity, and accuracy for detecting pulmonary KS. SPECT is more effective in detecting abnormal lymph nodes, pleural/pericardial effusions, and ascites. 99mTc-MIBI SPECT followed by planar imaging at 40-60 min can be useful in assessing pulmonary KS.

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.