Assessing the outcomes of HIV-infected persons receiving treatment for Kaposi sarcoma in Conakry-Guinea

Epidemic Kaposi sarcoma (KS) is the most common neoplasm in persons living with the human immunodeficiency virus (HIV) worldwide. Sub-Saharan Africa (SSA) with a high burden of both HIV and human herpesvirus-8 (HHV-8) infections coupled with a more limited access to antiretroviral therapy (ART), still witnesses a high incidence of KS [1, 2]. Treatment response and survival outcomes also remain challenging in SSA. In a large community-based sample of patients diagnosed with KS in SSA, almost half became lost to follow-up by two years [3]. However, excellent clinical outcomes and retention in care have also been reported especially with the use of newer chemotherapeutic agents in combination with ART [4, 5].

The prevalence of human immunodeficiency virus (HIV) in Guinea remains low at approximately 1.6% in 2014 but treatment coverage also remains among the lowest in the world, with less than one in four (23%) people living with HIV accessing antiretroviral therapy (ART) [6, 7]. Voluntary HIV testing that aims for early diagnosis also remains low at approximately 4.8%. Consequently, about 82% of HIV-infected persons diagnosed in healthcare facilities are already in advanced stages of the disease [8, 9]. The burden of acquired immune deficiency syndrome (AIDS)-defining diseases like Kaposi sarcoma (KS) and cryptococcal meningitis remains alarmingly high in Guinea despite recent strides made by the country against HIV/AIDS [8, 10].

Kaposi sarcoma is the third major cause of hospital admissions and the leading cause of death at the Dermatology Unit of Donka National Hospital (DNH) in Conakry [11]. Even though antiretroviral drugs (ARVs) are provided free of charge, patients often have to pay out of pocket for other essential care such as laboratory tests and essential drugs including medicines for opportunistic infections and KS. The country is still recovering from an unprecedented large outbreak of Ebola virus disease that seriously impacted the already fragile health system and represented a major setback in the fight against HIV [12, 13]. The Ebola epidemic drew the attention of several international partners to support the global response to the crisis, and to aim to rebuild a more resilient health system. However, only a few international organisations are supporting the fight against HIV/AIDS.

In response to what may be considered as a neglected HIV epidemic in Guinea, Médecins Sans Frontières (MSF) has been working in the country since 1984, providing HIV services since the introduction of ART in 2003. Currently, in collaboration with the Ministry of Health, MSF provides support to over 8000 HIV patients (about a quarter of the national ART cohort). MSF has also been supporting chemotherapeutic care for patients with KS at DNH since 2012. Preliminary results in 2013 were encouraging, as 14 and 8 cases out of a selected 29 were reported to have demonstrated complete and partial remissions, respectively, after a round of 12 cycles of chemotherapy combined with ART. However, the study sample was small, subject to selection bias and thus inadequate to influence operational or programmatic decisions [14]. Since then, a cumulative number of over 250 patients had been enrolled for hospital care for KS in the unit, with unknown outcomes. We thus aimed to assess the outcomes of these patients in the short and medium term, as a proxy measure to evaluate the performance of the project implemented between 2012 and 2015.

We aimed to evaluate the outcomes of patients treated for KS in a sub-Saharan African context, where a paucity of information on KS therapy exists. This is partly attributed to the scarcity of resources available for provision of KS treatment [18]. The study indicated that more patients were accessing treatment for KS than ever before and about one out of two patients had responded objectively to treatment. However, poor outcomes were also common as a result of late presentation and dropping out of care.

The number of patients seeking hospital care for KS at the Dermatology Unit of DNH has increased exponentially within the last few years. Between 2000 and 2009, about 134 patients were documented to have been enrolled in care [11], but we identified over 250 in the last four years. Elsewhere, the International Epidemiologic Databases to Evaluate AIDS (IeDEA) Consortia in the period 2009–2012 identified 677 cases from Kenya, 172 from Uganda, 57 from Nigeria, 67 from Cameroon and 355 from Malawi [3]. While East Africa is traditionally known as the hotbed of KS in the world [19, 20], the rising burden of KS in Guinea is consistent with the prevalent situation in the region where KS is the most commonly diagnosed malignancy associated with HIV. This is especially the case in West and Central Africa, where ART coverage remains low [6, 18, 21]. In Guinea, an increased ascertainment of KS and referral by physicians may be a contributing factor, together with an increased access to KS treatment, due to the support provided by MSF. Still, most patients presented not only with advanced HIV disease but also with an advanced KS, probably due to poor awareness or reliance on traditional medicine. The distance to travel to the capital city for those in remote areas might not only be a factor for late presentation, but also a contributor to early drop out from care and an obstacle for accessing treatment. This double burden of HIV/KS explains the high rates of attrition from care. Most late presenters could only benefit from palliative care to improve their quality of life. Under such circumstances, the goal of treatment may not be to achieve a high complete response rate but a high objective response rate (ORR = CR + PR), which is a surrogate endpoint for survival [22]. Thus, attaining an ORR of 52.4% in this cohort may be considered a satisfactory result for the patients, care givers and the programme. However, due to issues related to under- or overestimation of treatment effects, an ORR may not fully capture the net benefits of survival and should thus be interpreted with some caution [23]. We performed survival analyses based on Kaplan-Meier curves and Cox regression to demonstrate a correlation between treatment response and survival and, we observed that complete and partial responders lived longer than unknown or non-responders. Therefore, ORR could be a reliable marker of survival in advanced KS. This corroborates with findings from an earlier study on metastatic breast cancer [22]. We believe that defaulters with an unknown response and unknown vital status were probably non-responders and had died. This is because on one hand, they received only a median of two cycles of chemotherapy (treatment response was dose-dependent and vice versa); and on the other hand, the rate of attrition in the HIV cohort in Guinea at the same time was about 25% overall, which is much lower than the rate observed by the KS patients. Conversely, it was possible that some defaulters had responded at least partially to treatment before dropping out from care and thus resulting to an underestimation of the true overall response rate. This uncertainty might also explain the lack of precision (wide 95% CI) around the survival estimates between partial responders and non-responders (Table 3). Our overall findings seem to correlate with results from most other African countries where loss to follow up is very high and generally very poor KS treatment responses, though excellent outcomes have also been described in some African settings [3, 4, 21, 24]. Therefore, causes of loss to follow up should be investigated and strategies to mitigate them implemented.

The presence of woody oedema was a predictor of a poor treatment response. This form of skin thickening has been linked to long-standing skin oedema, and the resulting reactional inflammatory fibrosis is indicative of advanced disease or stage T1 [15]. Poor treatment outcomes have been reported in children and adolescents who presented with skin oedema in Malawi [25]. Clinicians need to identify KS at an early stage by raising their index of suspicion amongst other differential diagnoses in the presence of skin oedema, especially in patients infected with HIV.

Previous exposure to chemotherapy was also predictive of poor treatment response. It is very likely that this group of patients were restarting a treatment regimen that failed them earlier on, given that the country had few options for KS treatment. We recommend such patients to be candidates for second line therapy, which is now available in the form of pegylated liposomal doxorubicin (PLD). Although it is not certain that this will be successful because there have been no significant differences between various chemotherapy regimens in the treatment of severe or progressive Kaposi’s sarcoma in HIV-infected adults [26]. However, it is reasonable alternative to remove patients from a failed regimen and attempt other options.

Our study had some limitations. The diagnosis of KS was clinical rather than pathologic; while clinical diagnosis is very typical of SSA settings, and probably reasonably accurate in the correct context of HIV with classical skin lesions, it is clearly inaccurate with a recent study finding only 77% positive predictive value for clinically suspected KS compared to final histologic diagnosis in some East African HIV clinics [19]. The ACTG staging was incomplete and thus we could not account for disease severity in our attrition analyses. Treatment response was not ascertained for patients who dropped out of care, although we assumed with some degree of uncertainty that they were likely to have a progressive disease. This assumption must have led to an underestimation of the overall response rate. Treatment regimens varied between and within patients from one cycle to another, and it was therefore difficult to assess the effect of a single or combination therapy. The observed dose-response effect of chemotherapy appeared plausible but not causal because the temporal sequence of treatment duration and response could not be determined given the retrospective and incomplete nature of our data. A better response could as well have led to longer chemotherapy durations or cycles (and vice versa).

In conclusion, access to KS care has expanded in Guinea, and the overall response rate to KS treatment has been satisfactory. Poor outcomes are not uncommon and are largely due to late presentation and defaulting on treatment. Efforts towards early diagnosis and adherence to a complete series of chemotherapy are mandatory for optimising outcomes. Newer drugs may be required for patients previously exposed to chemotherapy.